Compositions and methods for the production of pyrimidine and pyridine compounds with BTK inhibitory activity

ABSTRACT

The present invention provides novel pyrimidine and pyridine compounds according to Formula (I), Formula (II), Formula (III), Formula (IV) and Formula (V) their manufacture and use for the treatment of hyperproliferative diseases including, but not limited to, cancer, lupus, allergic disorders, Sjogren&#39;s disease and rheumatoid arthritis. In preferred embodiments, the present invention describes irreversible kinase inhibitors including, but not limited to, inhibitors of Bruton&#39;s tyrosine kinase.

RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.15/417,953, filed on Jan. 27, 2017, which is a Divisional application ofU.S. patent application Ser. No. 14/727,050, filed on Jun. 1, 2015,which is a Continuation application of U.S. patent application Ser. No.14/112,428 (now U.S. Pat. No. 9,073,947), which is a U.S. national stageapplication of PCT International application PCT/US12/41803, filed onJun. 10, 2012, which claims the benefit of U.S. Provisional applicationNo. 61/495,773, filed on Jun. 10, 2011. The contents of theaforementioned are incorporated by reference in their entireties.

FIELD OF THE INVENTION

The invention relates to a series of pyrimidine and pyridine compoundsthat are useful as therapeutics in the treatment of a variety ofpathological conditions including (but not limited to) cancer,auto-immune disease, inflammatory diseases and neurodegenerativediseases in mammals. More particularly, embodiments of the presentinvention describe irreversible kinase inhibitors including, but notlimited to, inhibitors of Bruton's tyrosine kinase (hereinafter referredto as: “BTK”). Methods for the preparation of the aforementionedcompounds are disclosed in addition to the incorporation of thesecompounds into pharmaceutical compositions that include the same.Methods of using these BTK inhibitors are disclosed, alone or incombination with other therapeutic agents, for the treatment ofhyperproliferative diseases in mammals, especially humans, as well aspharmaceutical compositions which contain said inhibitors.

SUMMARY OF THE RELATED ART

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a wide variety of signaltransduction processes within the cell (Hardie, G. and Hanks, S. (1995)The Protein Kinase Facts Book. I and II, Academic Press, San Diego,Calif.). The kinases may be categorized into families by the substratesthey phosphorylate (e.g., protein-tyrosine, protein-serine/threonine,lipids, etc.). Sequence motifs have been identified that generallycorrespond to each of these kinase families (e.g., Hanks, S. K., Hunter,T., FASEB J., 9:576-596 (1995); Knighton, et al., Science, 253:407-414(1991); Hiles, et al., Cell, 70:419-429 (1992); Kunz, et al., Cell,73:585-596 (1993); Garcia-Bustos, et al., EMBO J., 13:2352-2361 (1994)).Protein kinases may be characterized by their regulation mechanisms.These mechanisms include, for example, autophosphorylation,transphosphorylation by other kinases, protein-protein interactions,protein-lipid interactions, and protein-polynucleotide interactions. Anindividual protein kinase may be regulated by more than one mechanism.

Kinases regulate many different cell processes including, but notlimited to, proliferation, differentiation, apoptosis, motility,transcription, translation and other signalling processes, by addingphosphate groups to target proteins. These phosphorylation events act asmolecular on/off switches that can modulate or regulate the targetprotein biological function. Phosphorylation of target proteins occursin response to a variety of extracellular signals (hormones,neurotransmitters, growth and differentiation factors, etc.), cell cycleevents, environmental or nutritional stresses, etc. The appropriateprotein kinase functions in signalling pathways to activate orinactivate (either directly or indirectly), for example, a metabolicenzyme, regulatory protein, receptor, cytoskeletal protein, ion channelor pump, or transcription factor. Uncontrolled signalling due todefective control of protein phosphorylation has been implicated in anumber of diseases, including, for example, inflammation, cancer,allergy/asthma, diseases and conditions of the immune system, diseasesand conditions of the central nervous system, and angiogenesis.

BTK, a member of the Tec family of non-receptor tyrosine kinases, is asignaling enzyme expressed in all hematopoietic cells types except Tlymphocytes and natural killer cells. BTK plays a well documented rolein the B-cell signaling pathway linking cell surface B-cell receptorstimulation to downstream intracellular responses. BTK is also aregulator of B-cell development, activation, signaling, and survival(Kurosaki, Curr Op Imm, 2000, 276-281; Schaeffer and Schwartzberg, CurrOp Imm 2000, 282-288). In addition, BTK exerts a physiological effectthrough other hematopoetic cell signaling pathways, e.g., Toll likereceptor (TLR) and cytokine receptor-mediated TNF-a production inmacrophages, IgE receptor (FcepsilonRI) signaling in Mast cells,inhibition of Fas/APO-1 apoptotic signaling in B-lineage lymphoid cells,and collagen-stimulated platelet aggregation. BTK has an ATP-bindingpocket with high similarity to Src-family kinases, such aslymphocyte-specific protein tyrosine kinase (Lck) and Lyn. Comparing BTKto other kinases one finds a conserved cysteine residue, Cys-481, in 11of 491 kinases, specifically members of the Tec and EGFR (epidermalgrowth factor receptor) kinase families.

BTK plays important roles in the development, differentiation,activation and proliferation of B cells, as well as their antibody andcytokine generation. In addition, Btk plays a central role in otherimmunological processes such as cytokine production by neutrophils, mastcells and monocytes, degranulation of neutrophils and mast cells as wellas differentiation/activation of osteoclasts. B-cell activation, breakof tolerance and auto-antibody production, on one hand and theproinflammatory milieu originated from exacerbated activation ofmonocytes, neutrophils and mast cells, on the other hand, are crucial inthe etiology of autoimmune diseases, including (but not limited to)rheumatoid arthritis and systemic lupus erythematosus.

Reversible kinase inhibitors have been developed into therapeuticcompounds. These reversible inhibitors, however, have decideddisadvantages. Many reversible inhibitors of kinases interact with theATP-binding site. Given the structure of the ATP-binding sites arehighly conserved among kinases, it has been difficult to develop areversible inhibitor that selectively inhibits a desired (i.e., target)kinase. Moreover, given that many reversible kinase inhibitors readilydissociate from their target polypeptide(s), maintaining inhibition overextended periods of time can be difficult. When using reversible kinaseinhibitors as therapeutics, therefore, often times near toxic dosagesand/or frequent dosing is required to achieve the intended biologicaleffect.

What is needed, therefore, are irreversible kinase inhibitors thatcovalently bind to their target polypeptide(s) without (substantially)binding to off-target polypeptides and, thereby, exerting undesirableoff-target effects.

DESCRIPTION OF THE INVENTION

The present invention provides a series of novel pyrimidine and pyridinekinase inhibitors. In some embodiments said kinase inhibitors areirreversible inhibitors of tyrosine kinases. In preferred embodiments,said irreversible kinase inhibitors inhibit BTK. While it is notintended that the compounds described by the present invention belimited to any specific mechanism of action, in some embodiments saidirreversible kinase inhibitors exert a physiological effect by forming acovalent bond with Cys 481 in BTK. Significantly, this Cys 481 in BTKfinds homologs in other kinases. Embodiments of the present inventionalso described methods for synthesizing said irreversible inhibitors,methods for using said irreversible inhibitors in the treatment ofdiseases (including, but not limited to, cancer,auto-immune/inflammatory diseases, and neurodegenerative diseases).Further described are pharmaceutical Formulations that include anirreversible kinase inhibitor including pharmaceutically acceptablesalts, solvates or prodrugs thereof, that are kinase inhibitors anduseful in the treatment of the above mentioned diseases.

The pyrimidine and pyridine kinase inhibitors of the present inventionare defined by Formula (I):

-   -   in which:    -   X denotes CH or N,    -   R¹ denotes NH₂, CONH₂ or H,    -   R² denotes Hal, Ar¹ or Het¹,    -   R³ denotes NR⁵[C(R⁵)₂]_(n)Het², NR⁵[C(R⁵)₂]_(n)Cyc, Het²,        O[C(R⁵)₂]_(n)Ar², NR⁵[C(R⁵)₂]_(n)Ar², O[C(R⁵)₂]_(n)Het²,        NR⁵(CH₂)_(p)NR⁵R⁶, O(CH₂)_(p)NR⁵R⁶ or NR⁵(CH₂)_(p)CR⁷R⁸NR⁵R⁶,    -   R⁴ denotes H, CH₃ or NH₂,    -   R⁵ denotes H or alkyl having 1, 2, 3 or 4 C atoms,    -   R⁶ N(R⁵)₂CH₂CH═CHCONH, Het³CH₂CH═CHCONH, CH₂═CHCONH(CH₂)_(n),        Het⁴(CH₂)_(n)COHet³-diyl-CH₂CH═CHCONH, HC≡CCO, CH₃C≡CCO,        CH₂═CH—CO, CH₂═C(CH₃)CONH, CH₃CH═CHCONH(CH₂)_(n),        N≡CCR⁷R⁸CONH(CH₂)_(n), Het⁴NH(CH₂)_(p)COHet³-diyl-CH₂CH≡CHCONH,        Het⁴(CH₂)_(p)CON        H(CH₂CH₂O)_(p)(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH, CH₂═CHSO₂,        ACH═CHCO, CH₃CH═CHCO,        Het⁴(CH₂)_(p)CONH(CH₂)_(p)Het³-diyl-CH₂CH═CHCONH, Ar³CH═CHSO₂,        CH₂═CHSO₂NH or N(R⁵)CH₂CH═CHCO,    -   R⁷, R⁸ denote together alkylene having 2, 3, 4, or 5 C atoms,    -   Ar¹ denotes phenyl or naphthyl, each of which is unsubstituted        or mono-, di- or trisubstituted by R⁶, Hal, (CH₂)_(n)NH₂,        CONHAr³, (CH₂)_(n)NHCOA, O(CH₂)_(n)Ar³, OCyc, A, COHet³, OA        and/or OHet³ (CH₂),    -   Ar² denotes phenyl, naphthyl or pyridyl each of which is        unsubstituted or mono-, di- or trisubstituted by R⁶, Hal, OAr³,        (CH₂)_(n)NH₂, (CH₂)_(n)NHCOA and/or Het³,    -   Ar³ denotes phenyl, which is unsubstituted or mono-, di- or        trisubstituted by OH, OA, Hal, CN and/or A,    -   Het¹ denotes a mono- or bicyclic saturated, unsaturated or        aromatic heterocycle having 1 to 4 N, O and/or S atoms, which        may be unsubstituted or mono-, di- or trisubstituted by R⁶,        O(CH₂)_(n)Ar³ and/or (CH₂)_(n)Ar³,    -   Het² denotes a mono- or bicyclic saturated heterocycle having 1        to 4 N, O and/or S atoms, which may be unsubstituted or mono-,        di- or trisubstituted by R⁶, Het³, CycSO₂, OH, Hal, COOH, OA,        COA, COHet³, CycCO, SO₂ and/or ═O,    -   Het³ denotes a monocyclic unsaturated, saturated or aromatic        heterocycle having 1 to 4 N, O and/or S atoms, which may be        unsubstituted or mono-, di- or trisubstituted by Hal, A and/or        ═O,    -   Het⁴ denotes a bi- or tricyclic unsaturated, saturated or        aromatic heterocycle having 1 to 4 N, O and/or S atoms, which        may be unsubstituted or mono-, di-, tri- or tetrasubstituted by        A, NO₂, Hal and/or ═O,    -   Cyc denotes cyclic alkyl having 3, 4, 5 or 6 C atoms, which is        unsubstituted, monosubstituted or disubstituted by R⁶ and/or OH        and which may comprise a double bond,    -   A denotes unbranched or branched alkyl having 1-10 C atoms, in        which 1-7H atoms may be replaced by F and/or Cl and/or in which        one or two non-adjacent CH₂ and/or CH-groups may be replaced by        O, NH and/or by N,    -   Hal denotes F, Cl, Br or I,    -   n denotes 0, 1, 2, 3 or 4,    -   p denotes 1, 2, 3, 4, 5 or 6,    -   and pharmaceutically usable salts, tautomers and stereoisomers        thereof, including mixtures thereof in all ratios.

In general, all residues which occur more than once may be identical ordifferent, i.e. are independent of one another. In other embodiments,the residues and parameters have the meanings indicated for the Formula(I), unless expressly indicated otherwise.

Further preferred are compounds of Subformulae 1 to 7 of Formula (I), inwhich the residues not designated in greater detail have the meaningindicated for the preferred group of compounds above, andpharmaceutically acceptable salts, solvates, solvates of salts, orprodrugs thereof, wherein:

In Subformula 1, Het¹ denotes piperidinyl, piperazinyl, pyrrolidinyl,morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl,tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl,benzimidazolyl, benzotriazolyl, indolyl, benzo-1,3-dioxolyl, indazolyl,azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl, imidazolidinyl,azetidinyl, azepanyl, benzo-2,1,3-thiadiazolyl, tetrahydrofuryl,dioxolanyl, tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl,dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl, dihydropyridylor dihydrobenzodioxinyl, each of which is unsubstituted or mono-, di- ortrisubstituted by R⁶, O(CH₂)_(n)Ar³ and/or (CH₂)_(n)Ar³.

In Subformula 2, Het¹ denotes pyrazolyl, pyridyl, pyrimidinyl,dihydropyridyl or dihydrobenzodioxinyl, each of which is unsubstitutedor mono-, di- or trisubstituted by R⁶, O(CH₂)_(n)Ar³ and/or(CH₂)_(n)Ar³.

In Subformula 3, Het² denotes piperidinyl, piperazinyl, pyrrolidinyl,morpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl,2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[4.5]decyl,2,7-diazaspiro[4.4]nonyl, 3-azabicylo[3.1.0]hexyl,2-azaspiro[3.3]heptyl, 6-azaspiro[3.4]octyl, 7-azaspiro[3.5]nonyl,5-azaspiro[3.5]nonyl, imidazolidinyl, azetidinyl, azepanyl,tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, tetrahydroimidazolyl,tetrahydropyrazolyl, tetrahydropyridyl, each of which is unsubstitutedor mono-, di- or trisubstituted by R⁶, Het³, CycSO₂, OH, OA, COA,COHet³, CycCO, SO₂ and/or ═O.

In Subformula 4, Het³ denotes piperidinyl, piperazinyl, pyrrolidinyl,morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl,tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl,imidazolidinyl, azetidinyl, azepanyl, tetrahydrofuryl, dioxolanyl,tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl,dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl ordihydropyridyl, each of which may be unsubstituted or mono-, di- ortrisubstituted by Hal, A and/or ═O.

In Subformula 5, Het³ denotes piperidinyl, pyrrolidinyl, morpholinyl,furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl,dihydropyrrolyl, dihydropyrazolyl or dihydropyridyl, each of which maybe unsubstituted or mono-, di- or trisubstituted by Hal, A and/or ═O.

In Subformula 6, Het⁴ denotes hexahydrothieno[3,4-d]imidazolyl,benzo[c][1,2,5]oxadiazolyl or5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-uidyl, each ofwhich may be unsubstituted or mono-, di-, tri- or tetrasubstituted by A,NO₂, Hal and/or ═O.

In Subformula 7, selected substituents of Formula I are further definedsuch that:

-   -   X denotes CH or N,    -   R¹ denotes NH₂, CONH₂ or H,    -   R² denotes Hal, Ar¹ or Het¹,    -   R³ denotes NR⁵[C(R⁵)₂]_(n)Het², NR⁵[C(R⁵)₂]_(n)Cyc, Het²,        O[C(R⁵)₂]_(n)Ar², NR⁵[C(R⁵)₂]_(n)Ar², O[C(R⁵)₂]_(n)Het²,        NR⁵(CH₂)_(p)NR⁵R⁶, O(CH₂)_(p)NR⁵R⁶ or NR⁵(CH₂)_(p)CR⁷R⁸NR⁵R⁶,    -   R⁴ denotes H,    -   R⁵ denotes H or alkyl having 1, 2, 3 or 4 C atoms,    -   R⁶ N(R⁵)₂CH₂CH═CHCONH, Het³CH₂CH═CHCONH, CH₂═CHCONH(CH₂)_(n),        Het⁴(CH₂)_(n)COHet³-diyl-CH₂CH═CHCONH, HC≡CCO, CH₃C≡CCO,        CH₂═CH—CO, CH₂═C(CH₃)CONH, CH₃CH═CHCONH(CH₂)_(n),        N═CCR⁷R⁸CONH(CH₂)_(n), Het⁴NH(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH,        Het⁴(CH₂)_(p)CON        H(CH₂CH₂O)_(p)(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH, CH₂═CHSO₂,        ACH═CHCO, CH₃CH═CHCO,        Het⁴(CH₂)_(p)CONH(CH₂)_(p)Het³-diyl-CH₂CH═CHCONH, Ar³CH═CHSO₂,        CH₂═CHSO₂NH or N(R⁵)CH₂CH═CHCO,    -   R⁷, R⁸ denote together alkylene having 2, 3, 4, or 5 C atoms,    -   Ar¹ denotes phenyl or naphthyl, each of which is unsubstituted        or mono-, di- or trisubstituted by R⁶, Hal, (CH₂)_(n)NH₂,        CONHAr³, (CH₂)_(n)NHCOA, O(CH₂)_(n)Ar³, OCyc, A, COHet³, OA        and/or OHet³ (CH₂),    -   Ar² denotes phenyl or naphthyl, each of which is unsubstituted        or mono-, di- or trisubstituted by R⁶, Hal, OAr³, (CH₂)_(n)NH₂,        (CH₂)_(n)NHCOA and/or Het³,    -   Ar³ denotes phenyl, which is unsubstituted or mono-, di- or        trisubstituted by OH, OA, Hal, CN and/or A,    -   Het¹ denotes piperidinyl, piperazinyl, pyrrolidinyl,        morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,        oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,        pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,        pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl,        benzo-1,3-dioxolyl, indazolyl, azabicyclo[3.2.1]octyl,        aza-bicyclo[2.2.2]octyl, imidazolidinyl, azetidinyl, azepanyl,        benzo-2,1,3-thiadiazolyl, tetrahydrofuryl, dioxolanyl,        tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl,        dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl,        dihydropyridyl or dihydrobenzodioxinyl, each of which is        unsubstituted or mono-, di- or trisubstituted by R⁶,        O(CH₂)_(n)Ar³ and/or (CH₂)_(n)Ar³,    -   Het² denotes piperidinyl, piperazinyl, pyrrolidinyl,        morpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl,        2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[4.5]decyl,        2,7-diazaspiro[4.4]nonyl, 3-azabicylo[3.1.0]hexyl,        2-azaspiro[3.3]heptyl, 6-azaspiro[3.4]octyl,        7-azaspiro[3.5]nonyl, 5-azaspiro[3.5]nonyl, imidazolidinyl,        azetidinyl, azepanyl, tetrahydrofuryl, dioxolanyl,        tetrahydrothienyl, tetrahydroimidazolyl, tetrahydropyrazolyl,        tetrahydropyridyl, each of which is unsubstituted or mono-, di-        or trisubstituted by R⁶, Het³, CycSO₂, OH, OA, COA, COHet³,        CycCO, SO₂ and/or ═O,    -   Het³ denotes piperidinyl, piperazinyl, pyrrolidinyl,        morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,        oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,        pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,        pyridazinyl, pyrazinyl, imidazolidinyl, azetidinyl, azepanyl,        tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, dihydropyrrolyl,        tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl,        tetrahydropyridyl or dihydropyridyl, each of which may be        unsubstituted or mono-, di- or trisubstituted by Hal, A and/or        ═O,    -   Het⁴ denotes hexahydrothieno[3,4-d]imidazolyl,        benzo[c][1,2,5]oxadiazolyl or        5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-uidyl, each        of which may be unsubstituted or mono-, di-, tri- or        tetrasubstituted by A, NO₂, Hal and/or ═O,    -   Cyc denotes cyclic alkyl having 3, 4, 5 or 6 C atoms, which is        unsubstituted or monosubstituted by R⁶ and which may comprise a        double bond,    -   A denotes unbranched or branched alkyl having 1-10 C atoms, in        which 1-7H atoms may be replaced by F and/or Cl and/or in which        one or two non-adjacent CH₂ and/or CH-groups may be replaced by        O, NH and/or by N,    -   Hal denotes F, Cl, Br or I,    -   n denotes 0, 1, 2, 3 or 4,    -   p denotes 1, 2, 3, 4, 5 or 6.

In some embodiments of the present invention, the pyrimidine andpyridine kinase inhibitors of the present invention are also defined byFormula (II):

-   and pharmaceutically acceptable salts, solvates, solvates of salts,    or prodrugs thereof,-   wherein:-   X is H or CH₃ or NH₂,-   Y is H, Hal or is absent,-   B is N or CH,-   E is NH₂ or H,-   W is NR, O or a cyclic amine,-   Z is, independently, CH₂, CH₃, CH₂—CH₂, CH—CH₂, H, NH or is absent,-   “linker” is (CH₂)_(n), wherein: _(n) is 1, 2 or 3 or an optionally    substituted group selected from a phenyl ring, an aryl ring,    heteroaryl ring, branched or unbranched alkyl group, a 5-6 membered    monocyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, or oxygen, a 4-7 membered saturated or    partially unsaturated heterocycle having 1-3 heteroatoms    independently selected from nitrogen, or oxygen, or a 7-10 membered    bicyclic saturated or partially unsaturated heterocyclic ring having    1-5 heteroatoms independently selected from nitrogen, or oxygen, or    a 7-10 membered bicyclic saturated or partially unsaturated    heterocyclic ring having 1-5 heteroatoms attached to a hetero    saturated ring. Linkers may also be cycloalkanes optionally    substituted by heteroatoms (independently selected from nitrogen, or    oxygen), cycloalkanes optionally substituted with —NH or OH, fused    or bridged rings or optionally substituted spirocyclic rings that    optionally contain heteroatoms,-   A is a mono- or bicyclic aromatic homo- or heterocycle having 0, 1,    2, 3 or 4 N, and/or O atoms and 5, 6, 7, 8, 9, or 10 skeleton C    atoms, which may be unsubstituted or, independently of one another,    mono-, di- or trisubstituted by Hal, OH or OR,-   Hal is F, Cl, Br or I,-   R is independently hydrogen, oxygen or an optionally substituted    group selected from C₁₋₆ linear or cyclic aliphatic, benzyl, phenyl,    a phenyl group optionally substituted with 1, 2 or 3 O atoms, a 4-7    membered heterocylic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, or a 5-6 membered monocyclic    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, or oxygen or a mono- or bicyclic aromatic homo- or    heterocycle having 0, 1, 2, 3 or 4 N, O atoms and 5, 6, 7, or 8 C    skeleton atoms, which may be unsubstituted or, independently of one    another, mono-, di- or trisubstituted by Hal, A, OH, NH₂, nitrile,    and/or CH(Hal)₃ or is an unbranched or branched linear alkyl having    1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH₂ groups may    be replaced by an O atom and/or by an —NH—, —CO—, —NHCOO—, —NHCONH—,    —CONH—, —NHCO— or —CH═CH— group, and in which 1-3H atoms may be    replaced by Hal,-   R^(q) is selected from —R, -A, halogen, —OR, —O(CH₂)_(r)OR, —R(NH),    —NO₂, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)NR₂, —NRSO₂R, or    —N(R)₂,-   r is 1-4,-   n is 0-4, and-   Q is an electrophilic group such as those listed in Table 1 wherein    said electrophilic groups may further comprise a warhead.

As used herein the term “warhead” refers to a part, functional group orsubstituent of the compounds as claimed in the present invention,wherein, said part, functional group or substituent covalently binds toan amino acid (such as cysteine, lysine, or any other amino acid, eithernative or modified, that can form said covalent bond) that is present,for example, in the binding region within a given ligand wherein saidwarhead binds with said ligand, wherein the covalent binding betweensaid warhead and the binding region of said target protein occurs underconditions wherein a physiological function of said protein isirreversibly inhibited.

While it is not intended that the present invention be limited to aspecific group for substituent Q, as set out in Formula (II) above, incertain embodiments substituent Q is selected from the groups set out inTable 1. All compounds, in Table 1, appearing within a box are not“warheads” as defined above.

TABLE 1

wherein, “

” denotes the bonding point of Q to Z in Formula (II).

In other embodiments, the pyrimidine and pyridine kinase inhibitors ofthe present invention are defined by Formula (III):

-   and pharmaceutically acceptable salts, solvates, solvates of salts,    or prodrugs thereof,-   wherein:-   X is O or NH,-   Y is N or CH,-   W is H, NH₂ or CONH₂,-   Q is H or NH₂,-   R¹ is L¹-R⁴-L²-R⁵,-   R² is M¹-S⁴-M²-S⁵-   L¹ is a single bond, methylene, or cyclic A which may be mono- or    disubstituted with N or NH₂,-   R⁴ is Ar, A or cyclic A which may be mono- or disubstituted with N,    —O— or Hal,-   R⁵ is Ar, A or cyclic A which may be mono- or disubstituted with N,    —O— or Hal or is absent. In preferred embodiments, R⁵ is selected    from the group consisting of 2-fluoropyridine,    1-methylpyridin-2(1H)-one and 2-chloropyridine,-   L² is H, —O—, substituted or unsubstituted C₁-C₄alkyl, substituted    or unsubstituted C₁-C₄ heteroalkyl, C₁-C₆alkoxyalkyl,    C₁-C₈alkylaminoalkyl, substituted or unsubstituted aryl, substituted    or unsubstituted heteroaryl, C₁-C₄alkyl(aryl),    C₁-C₄alkyl(heteroaryl), C₁-C₄alky(C₃-C₈cycloalkyl), or    C₁-C₄alkyl(C₂-C₈heterocycloalkyl). In some embodiments, L² is    —CH₂—O—(C₁₋C₃alkyl), —CH₂—N(C₁-C₃alkyl)₂, C₁-C₄alkyl(phenyl), or    C₁-C₄alkyl (5- or 6-membered heteroaryl). In some embodiments L² is    -A-. In some embodiments L² is absent. In preferred embodiments of    the present invention L² is selected from the group consisting of    but-3-en-2-one, propan-2-one, (E)-5-(dimethylamino)pent-3-en-2-one,    (E)-pent-3-en-2-one, pent-3-yn-2-one, 1-chloropropan-2-one,    (methylsulfonyl)ethane,    (E)-5-((2-methoxyethyl)(methyl)amino)pent-3-en-2-one or    (Z)-pent-3-en-2-one,-   M¹ is a single bond,-   S⁴ is Ar, A or cyclic A which may be mono- or disubstituted with N,    —O— or Hal. In preferred embodiments of the present invention S⁴ is    a heteroaromatic 5 to 6 member ring,-   M² O, NH, CH₂ or is absent,-   S⁵ is H, Ar, A or cyclic A which may be mono- or disubstituted with    N, —O—, Hal. In certain embodiments of the present invention S⁵ is    selected from the group consisting of but-3-en-2-one, benzene,    (E)-5-(dimethylamino)pent-3-en-2-one, ethylbenzene,    1-ethyl-2-methoxybenzene, aniline and    (E)-5-morpholinopent-3-en-2-one. In some embodiments of the present    invention S₅ is absent,-   Ar is a mono- or bicyclic aromatic homo- or heterocycle having 0, 1,    2, 3 or 4 N, and/or O atoms and 5, 6, 7, 8, 9, or 10 skeleton atoms,    which may be unsubstituted or, independently of one another, mono-,    di- or trisubstituted by Hal, A, OH, OA, NH₂, NHA, NA₂, NO₂, CN,    OCN, COOH, COOA, CONH₂, CONHA, CONA₂, NHCOA, NHCONHA, NHCONH, CHO    and/or COA, and in which a ring N-atom may be substituted by an    O-atom to form an N-oxide group and in which in the case of a    bicyclic aromatic cycle on of the two rings may be partly saturated,-   A is unbranched or branched linear or cyclic alkyl having 1, 2, 3,    4, 5, 6, 7 or 8 C atoms, in which one or two CH₂ groups may be    replaced by an O atom and/or by an —NH—, —CO—, —NHCOO—, —NHCONH—.    —N(LA)-, —CONH—, —NHCO— or —CH═CH— group,-   LA is unbranched or branched, linear alkyl having 1, 2, 3 or 4 C    atoms, wherein 1, 2 or 3H atoms may be replaced by Hal,-   Hal is F, Cl, Br or I.

In some embodiments, the pyrimidine and pyridine kinase inhibitors ofthe present invention are also defined by Formula (IV):

-   and pharmaceutically acceptable salts, solvates, solvates of salts,    or prodrugs thereof,-   wherein:-   Z is N or CH,-   X is O or NH, and-   R³ is selected from the group consisting of the following    structures:

-   wherein, “R” denotes the bonding point to Z in Formula IV.

In some embodiments, the pyrimidine and pyridine kinase inhibitors ofthe present invention are also defined by Formula (V):

-   and pharmaceutically acceptable salts, solvates, solvates of salts,    or prodrugs thereof,    -   in which:    -   X denotes CH or N,    -   R¹ denotes NR⁵[C(R⁵)₂]_(n)Het²,    -   R² denotes Hal, Ar¹ or Het¹,    -   R³ denotes NH₂,    -   R⁴ denotes H, CH₃ or NH₂,    -   R⁵ denotes H or alkyl having 1, 2, 3 or 4 C atoms,    -   R⁶ N(R⁵)₂CH₂CH═CHCONH, Het³CH₂CH═CHCONH, CH₂═CHCONH(CH₂)_(n),        Het⁴(CH₂)_(n)COHet³-diyl-CH₂CH═CHCONH, HC≡CCO, CH₃C≡CCO,        CH₂═CH—CO, CH₂═C(CH₃)CONH, CH₃CH═CHCONH(CH₂)_(n),        N—CCR⁷R⁸CONH(CH₂)_(n), Het⁴NH(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH,        Het⁴(CH₂)_(p)CONH(CH₂CH₂O)_(p)(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH,        CH₂═CHSO₂, ACH═CHCO, CH₃CH═CHCO,        Het⁴(CH₂)_(p)CONH(CH₂)_(p)Het³-diyl-CH₂CH═CHCONH, Ar³CH═CHSO₂,        CH₂═CHSO₂NH or N(R⁵)CH₂CH═CHCO,    -   R⁷, R⁸ denote together alkylene having 2, 3, 4, or 5 C atoms,    -   Ar¹ denotes phenyl or naphthyl, each of which is unsubstituted        or mono-, di- or trisubstituted by R⁶, Hal, (CH₂)_(n)NH₂,        CONHAr³, (CH₂)_(n)NHCOA, O(CH₂)_(n)Ar³, OCyc, A, COHet³, OA        and/or OHet³ (CH₂),    -   Ar² denotes phenyl, naphthyl or pyridyl each of which is        unsubstituted or mono-, di- or trisubstituted by R⁶, Hal, OAr³,        (CH₂)_(n)NH₂, (CH₂)_(n)NHCOA and/or Het³,    -   Ar³ denotes phenyl, which is unsubstituted or mono-, di- or        trisubstituted by OH, OA, Hal, CN and/or A,    -   Het¹ denotes a mono- or bicyclic saturated, unsaturated or        aromatic heterocycle having 1 to 4 N, O and/or S atoms, which        may be unsubstituted or mono-, di- or trisubstituted by R⁶,        O(CH₂)_(n)Ar³ and/or (CH₂)_(n)Ar³,    -   Het² denotes a mono- or bicyclic saturated heterocycle having 1        to 4 N, O and/or S atoms, which may be unsubstituted or mono-,        di- or trisubstituted by R⁶, Het³, CycSO₂, OH, Hal, COOH, OA,        COA, COHet³, CycCO, SO₂ and/or ═O,    -   Het³ denotes a monocyclic unsaturated, saturated or aromatic        heterocycle having 1 to 4 N, O and/or S atoms, which may be        unsubstituted or mono-, di- or trisubstituted by Hal, A and/or        ═O,    -   Het⁴ denotes a bi- or tricyclic unsaturated, saturated or        aromatic heterocycle having 1 to 4 N, O and/or S atoms, which        may be unsubstituted or mono-, di-, tri- or tetrasubstituted by        A, NO₂, Hal and/or ═O,    -   Cyc denotes cyclic alkyl having 3, 4, 5 or 6 C atoms, which is        unsubstituted, monosubstituted or disubstituted by R⁶ and/or OH        and which may comprise a double bond,    -   A denotes unbranched or branched alkyl having 1-10 C atoms, in        which 1-7H atoms may be replaced by F and/or Cl and/or in which        one or two non-adjacent CH₂ and/or CH-groups may be replaced by        O, NH and/or by N,    -   Hal denotes F, Cl, Br or I,    -   n denotes 0, 1, 2, 3 or 4,    -   p denotes 1, 2, 3, 4, 5 or 6,    -   and pharmaceutically usable salts, tautomers and stereoisomers        thereof, including mixtures thereof in all ratios.

In general, all residues which occur more than once may be identical ordifferent, i.e. are independent of one another. Above and below, theresidues and parameters have the meanings indicated for Formula (I),Formula (II), Formula (III), Formula (IV) and Formula (V) unlessexpressly indicated otherwise. Accordingly, the invention relates, inparticular, to the compounds of Formula (I), Formula (II), Formula(III), Formula (IV) and Formula (V) in which at least one of the saidresidues has one of the preferred meanings indicated below.

The term “substituted” preferably relates to the substitution by theabove-mentioned substituents, where a plurality of different degrees ofsubstitution are possible, unless indicated otherwise.

All physiologically acceptable salts, derivatives, solvates, solvates ofsalts, and stereoisomers of these compounds, including mixtures thereofin all ratios, are also in accordance with the invention.

The compounds of the Formula (I), (II), (III), (IV) and (V) may have oneor more centres of chirality. They may accordingly occur in variousenantiomeric forms and be in racemic or optically active form. Theinvention therefore also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andhydrates and solvates of these compounds.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the R andS forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitably N-protected amino acids(for example N-benzoylproline or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/acetonitrile, for example in theratio 82:15:3.

An elegant method for the resolution of racemates containing estergroups (for example acetyl esters) is the use of enzymes, in particularesterases.

It is also contemplated that compounds of Formula (I), Formula (II),Formula (III), Formula (IV) and Formula (V) include isotope-labeledforms thereof. An isotope-labeled form of a compound of Formula (I),Formula (II), Formula (III), Formula (IV) and Formula (V) is identicalto this compound apart from the fact that one or more atoms of thecompound have been replaced by an atom or atoms having an atomic mass ormass number which differs from the atomic mass or mass number of theatom which usually occurs naturally. Examples of isotopes which arereadily commercially available and which can be incorporated into acompound of the Formula I by well-known methods include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine,for example ²H, ³H, ¹³, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl,respectively. It is also contemplated that a compound of the Formula I,a prodrug, thereof or a pharmaceutically acceptable salt of either whichcontains one or more of the above-mentioned isotopes and/or otheriso-topes of other atoms are embodiments of the present invention. Anisotope-labeled compound of the Formula I can be used in a number ofbeneficial ways. For example, an isotope-labeled compound of the FormulaI into which, for example, a radioisotope, such as ³H or ¹⁴C, has beenincorporated, is suitable for medicament and/or substrate tissuedistribution assays. These radioisotopes, i.e. tritium (³H) andcarbon-14 (¹⁴C), are particularly preferred owing to their ease ofpreparation and excellent detectability. Incorporation of heavierisotopes, for example deuterium (²H), into a compound of the Formula Imay have therapeutic advantages owing to the higher metabolic stabilityof this isotope-labeled compound. Higher metabolic stability translatesdirectly into an increased in vivo half-life or lower dosages, whichunder some circumstances would represent a preferred embodiment of thepresent invention. An isotope-labeled compound of the Formula I canadapted to the procedures disclosed in the synthesis schemes and therelated description, in the example part and in the preparation part inthe present text, replacing a non-isotope-labeled reactant by a readilyavailable isotope-labeled reactant.

In other embodiments it is contemplated that deuterium (²H) may beincorporated into a compound of Formula (I), Formula (II), Formula(III), Formula (IV) and Formula (V). Such deuterated compounds canmodify the oxidative metabolism of said deuterated compound by means theprimary kinetic isotope effect. The primary kinetic isotope effect is achange of the rate for a chemical reaction that results from exchange ofisotopic nuclei, which in turn is caused by the change in ground stateenergies necessary for covalent bond formation after this isotopicexchange. Exchange of a heavier isotope usually results in a lowering ofthe ground state energy for a chemical bond and thus causes a reductionin the rate in rate-limiting bond breakage. If the bond breakage occursin or in the vicinity of a saddle-point region along the coordinate of amulti-product reaction, the product distribution ratios can be alteredsubstantially. For explanation: if deuterium is bonded to a carbon atomat a non-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. If this rate difference is observed in any compounds of Formula(I), Formula (II), Formula (III), Formula (IV) and Formula (V)susceptible to oxidation, the profile of this compound, in vivo, can bedrastically modified and result in improved pharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilledin the art attempts to optimize pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays known in the aremay provide valuable information on the course of oxidative metabolismof this type, which in turn permits the rational design of deuteratedcompounds of Formula (I), Formula (II), Formula (III), Formula (IV) andFormula (V) with improved stability through resistance to said oxidativemetabolism. Significant improvements in the pharmacokinetic profiles ofcompounds of the Formula I may thereby be obtained, and can be expressedquantitatively in terms of increases in the in vivo half-life (t/2),concentration at maximum therapeutic effect (C_(max)), area under thedose response curve (AUC), and F; and in terms of reduced clearance,dose and materials costs.

While it is not intended that the present invention be limited to anydeuterated motif, the following is an example. A compound of Formula(I), Formula (II), Formula (III), Formula (IV) and Formula (V) which hasmultiple potential sites of attack for oxidative metabolism, for examplebenzylic hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, isprepared as a series of analogues in which various combinations ofhydrogen atoms are replaced by deuterium atoms, so that some, most orall of these hydrogen atoms have been replaced by deuterium atoms.Half-life determinations enable favorable and accurate determination ofthe extent of the extent to which the improve-ment in resistance tooxidative metabolism has improved. In this way, it can be determinedthat the half-life of the parent compound may be extended by up to 100%as the result of deuterium-hydrogen exchange of this type.

Deuterium-hydrogen exchange in a compound of Formula (I), Formula (II),Formula (III), Formula (IV) and Formula (V) can also be used to achievea favorable modification of the metabolite spectrum of the startingcompound in order to diminish or eliminate undesired toxic metabolites.For example, if a toxic metabolite arises through oxidativecarbon-hydrogen (C—H) bond cleavage, it can reasonably be assumed thatthe deuterated analogue will greatly diminish or eliminate production ofthe unwanted metabolite, even if the particular oxidation is not arate-determining step. Further information on the state of the art withrespect to deuterium-hydrogen exchange may be found, for example inHanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J.Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985,Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al.Carcinogenesis 16(4), 683-688, 1993.

The compounds of the present invention can be in the form of a prodrugcompound. “Prodrug compound” means a derivative that is converted into abiologically active compound according to the present invention underphysiological conditions in the living body, e.g., by oxidation,reduction, hydrolysis or the like, each of which is carried outenzymatically, or without enzyme involvement. Examples of prodrugs arecompounds, wherein the amino group in a compound of the presentinvention is acylated, alkylated or phosphorylated, e.g.,eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein thehydroxyl group is acylated, alkylated, phosphorylated or converted intothe borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy,fumaryloxy, alanyloxy or wherein the carboxyl group is esterified oramidated, or wherein a sulfhydryl group forms a disulfide bridge with acarrier molecule, e.g. a peptide, that delivers the drug selectively toa target and/or to the cytosol of a cell. These compounds can beproduced from compounds of the present invention according to well-knownmethods. Other examples of prodrugs are compounds, wherein thecarboxylate in a compound of the present invention is for exampleconverted into an alkyl-, aryl-, choline-, amino, acyloxymethylester,linolenoyl-ester.

Metabolites of compounds of the present invention are also within thescope of the present invention.

Where tautomerism, e.g., keto-enol tautomerism, of compounds of thepresent invention or their prodrugs may occur, the individual forms,e.g., the keto or the enol form, are claimed separately and together asmixtures in any ratio. The same applies for stereoisomers, e.g.,enantiomers, cis/trans isomers, conformers and the like.

If desired, isomers can be separated by methods well known in the art,e.g. by liquid chromatography. The same applies for enantiomers, e.g.,by using chiral stationary phases. Additionally, enantiomers may beisolated by converting them into diastereomers, i.e., coupling with anenantiomerically pure auxiliary compound, subsequent separation of theresulting diastereomers and cleavage of the auxiliary residue.Alternatively, any enantiomer of a compound of the present invention maybe obtained from stereoselective synthesis using optically pure startingmaterials

The compounds of the present invention can be in the form of apharmaceutically acceptable salt or a solvate. The term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids, includinginorganic bases or acids and organic bases or acids. In cases where thecompounds of the present invention contain one or more acidic or basicgroups, the invention also comprises their correspondingpharmaceutically or toxicologically acceptable salts, in particulartheir pharmaceutically utilizable salts. Thus, the compounds of thepresent invention which contain acidic groups can be present in saltform, and can be used according to the invention, for example, as alkalimetal salts, alkaline earth metal salts or as ammonium salts. Moreprecise examples of such salts include sodium salts, potassium salts,calcium salts, magnesium salts or salts with ammonia or organic aminessuch as, for example, ethylamine, ethanolamine, triethanolamine or aminoacids. Compounds of the present invention which contain one or morebasic groups, i.e. groups which can be protonated, can be present insalt form, and can be used according to the invention in the form oftheir addition salts with inorganic or organic acids. Examples ofsuitable acids include hydrogen chloride, hydrogen bromide, phosphoricacid, sulfuric acid, nitric acid, methanesulfonic acid,p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, aceticacid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formicacid, propionic acid, pivalic acid, diethylacetic acid, malonic acid,succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid,sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid,isonicotinic acid, citric acid, adipic acid, and other acids known tothe person skilled in the art. If the compounds of the present inventionsimultaneously contain acidic and basic groups in the molecule, theinvention also includes, in addition to the salt forms mentioned, innersalts or betaines (zwitterions). The respective salts can be obtained bycustomary methods which are known to a person skilled in the art, forexample by contacting these with an organic or inorganic acid or base ina solvent or dispersant, or by anion exchange or cation exchange withother salts. The present invention also includes all salts of thecompounds of the present invention which, owing to low physiologicalcompatibility, are not directly suitable for use in pharmaceuticals butwhich can be used, for example, as intermediates for chemical reactionsor for the preparation of pharmaceutically acceptable salts.

Furthermore, the present invention relates to pharmaceuticalcompositions comprising a compound of the present invention, or aprodrug compound thereof, or a pharmaceutically acceptable salt orsolvate thereof as an active ingredient together with a pharmaceuticallyacceptable carrier.

“Pharmaceutical composition” means one or more active ingredients, andone or more inert ingredients that make up the carrier, as well as anyproduct which results, directly or indirectly, from combination,complexation or aggregation of any two or more of the ingredients, orfrom dissociation of one or more of the ingredients, or from other typesof reactions or interactions of one or more of the ingredients.Accordingly, the pharmaceutical compositions of the present inventionencompass any composition made by admixing a compound of the presentinvention and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the present invention may additionallycomprise one or more other compounds as active ingredients, such as oneor more additional compounds of the present invention, or a prodrugcompound or other BTK inhibitors.

The pharmaceutical compositions include compositions suitable for oral,rectal, topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

In one embodiment, said compounds and pharmaceutical composition are forthe treatment of cancer such as brain, lung, colon, epidermoid, squamouscell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney,liver, ovarian, prostate, colorectal, uterine, rectal, oesophageal,testicular, gynecological, thyroid cancer, melanoma, hematologicmalignancies such as acute myelogenous leukemia, multiple myeloma,chronic myelogneous leukemia, myeloid cell leukemia, glioma, Kaposi'ssarcoma, or any other type of solid or liquid tumors. Preferably, thecancer to be treated is chosen from breast, colorectal, lung, prostateor pancreatic cancer or glioblastoma.

The invention also relates to the use of compounds according to theinvention for the preparation of a medicament for the treatment ofhyperproliferative diseases related to the hyperactivity of BTK as wellas diseases modulated by the BTK cascade in mammals, or disordersmediated by aberrant proliferation, such as cancer or hyperactivity of Bcells, mast cells, neutrophils and monocytes such in inflammatoryconditions.

DESCRIPTION OF THE FIGURES

FIGS. 1 A and B present data evaluating a compound described by thepresent invention[1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one,designated as “CPD. B” in the figure] in an interferon-alpha acceleratedsystemic lupus erythematosus (SLE) mouse model.

FIG. 2 presents additional data evaluating a compound described by thepresent invention[1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one,designated as “CPD. B” in the figure] in an interferon-alpha acceleratedsystemic lupus erythematosus (SLE) mouse model.

FIG. 3 presents data evaluating a compound described by the presentinvention[1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one,designated as “CPD. A” in the figure] in a rat collagen-inducedarthritis model.

FIG. 4 presents data evaluating a compound described by the presentinvention[1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one,designated as “CPD. A” in the figure] in an interferon-alpha acceleratedsystemic lupus erythematosus (SLE) mouse model.

FIG. 5 presents data evaluating a compound described by the presentinvention[1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one,designated as “CPD. B” in the figure] in a mouse model of passivecutaneous anaphylaxis (PCA).

FIG. 6 presents data evaluating a compound described by the presentinvention[1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one]with regard to the ex vivo anti-IgD-induced CD69 upregulation in mousewhole blood.

The invention also relates to a compound or pharmaceutical compositionfor treating a disease related to vasculogenesis or angiogenesis in amammal which comprises a therapeutically effective amount of a compoundof the present invention, or a pharmaceutically acceptable salt, prodrugor hydrate thereof, and a pharmaceutically acceptable carrier.

In one embodiment, said compound or pharmaceutical composition is fortreating a disease selected from the group consisting of tumorangiogenesis, chronic inflammatory diseases such as rheumatoidarthritis, systemic lupus erythematosus, inflammatory bowel disease,Sjögren's Syndrome, atherosclerosis, skin and allegic diseases such aspsoriatic arthritis, psoriasis, eczema, and sclerodema, asthma andatopic dermatitis or diseases such as diabetes, diabetic retinopathy,retinopathy of prematurity and age-related macular degeneration.

In one embodiment the treatment of rheumatoid arthritis with BTKinhibitors is preferred given experimental validation which confirms theefficacy of BTK inhibitors in the treatment of collagen antibody inducedarthritis and collagen induced arthritis. Pan, Z. et al., Discovery ofSelective Irreversible Inhibitors of Brunton's Tyrosine Kinase.ChemMedChem 2, 58-61 (2007). More specifically treatment with BTKinhibitors have been show to reduce the incidence and severity ofcollagen induced arthritis and K/B×N serum induced arthritis.

This invention also relates to a compound or pharmaceutical compositionfor inhibiting abnormal cell growth in a mammal which comprises anamount of a compound of the present invention, or a pharmaceuticallyacceptable salt or solvate or prodrug thereof, in combination with anamount of another anti-cancer therapeutic, wherein the amounts of thecompound, salt, solvate, or prodrug, and of the chemotherapeutic aretogether effective in inhibiting abnormal cell growth. Many anti-cancertherapeutics are presently known in the art. In one embodiment, theanti-cancer therapeutic is a chemotherapeutic selected from the groupconsisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.In another embodiment the anti-cancer therapeutic is an antibodyselected from the group consisting of bevacizumab, CD40-specificantibodies, chTNT-1/B, denosumab, zanolimumab, IGF1R-specificantibodies, lintuzumab, edrecolomab, WX G250, rituximab, ticilimumab,trastuzumab and cetuximab. In yet another embodiment the anti-cancertherapeutic is an inhibitor of another protein kinase, auch as Akt, Axl,Aurora A, Aurora B, dyrk2, epha2, fgfr3, igf1r, IKK2, JNK3, Vegfr1,Vegfr2, Vegfr3 (also known as Flt-4), KDR, MEK, MET, Plk1, RSK1, Src,TrkA, Zap70, cKit, bRaf, EGFR, Jak2, PI3K, NPM-Alk, c-Abl, BTK, FAK,PDGFR, TAK1, LimK, Flt-3, PDK1 and Erk.

This invention further relates to a method for inhibiting abnormal cellgrowth in a mammal or treating a hyperproliferative disorder thatcomprises administering to the mammal an amount of a compound of thepresent invention, or a pharmaceutically acceptable salt or solvate orprodrug thereof, in combination with radiation therapy, wherein theamounts of the compound, salt, solvate, or prodrug, is in combinationwith the radiation therapy effective in inhibiting abnormal cell growthor treating the hyperproliferative disorder in the mammal. Techniquesfor administering radiation therapy are known in the art, and thesetechniques can be used in the combination therapy described herein. Theadministration of a compound of the invention in this combinationtherapy can be determined as described herein. It is believed that thecompounds of the present invention can render abnormal cells moresensitive to treatment with radiation for purposes of killing and/orinhibiting the growth of such cells.

Accordingly, this invention further relates to a method for sensitizingabnormal cells in a mammal to treatment with radiation which comprisesadministering to the mammal an amount of a compound of the presentinvention or pharmaceutically acceptable salt or solvate or prodrugthereof, which amount is effective is sensitizing abnormal cells totreatment with radiation. The amount of the compound, salt, or solvatein this method can be determined according to the means for ascertainingeffective amounts of such compounds described herein. The invention alsorelates to a method for inhibiting abnormal cell growth in a mammal thatcomprises an amount of a compound of the present invention, or apharmaceutically acceptable salt or solvate thereof, a prodrug thereof,or an isotopically-labeled derivative thereof, and an amount of one ormore substances selected from anti-angiogenesis agents, signaltransduction inhibitors, and antiproliferative agents.

In practical use, the compounds of the present invention can be combinedas the active ingredient in intimate admixture with a pharmaceuticalcarrier according to conventional pharmaceutical compounding techniques.The carrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like. In the case of oral liquidpreparations, any of the usual pharmaceutical media may be employed,such as, for example, suspensions, elixirs and solutions; or carrierssuch as starches, sugars, microcrystalline cellulose, diluents,granulating agents, lubricants, binders, disintegrating agents and thelike. In the case of oral solid preparations the composition may takeforms such as, for example, powders, hard and soft capsules and tablets,with the solid oral preparations being preferred over the liquidpreparations.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe coated by standard aqueous or nonaqueous techniques. Suchcompositions and preparations should contain at least 0.1 percent ofactive compound. The percentage of active compound in these compositionsmay, of course, be varied and may conveniently be between about 2percent to about 60 percent of the weight of the unit. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage will be obtained. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Compounds of the present invention may also be administeredparenterally. Solutions or suspensions of these active compounds can beprepared in water suitably mixed with a surfactant such ashydroxy-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols and mixtures thereof in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like. Preferably compounds of thepresent invention are administered orally.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.Such dosage may be ascertained readily by a person skilled in the art.

When treating or preventing cancer, inflammation or other proliferativediseases for which compounds of the present invention are indicated,generally satisfactory results are obtained when the compounds of thepresent invention are administered at a daily dosage of from about 0.01milligram to about 100 milligram per kilogram of animal body weight,preferably given as a single daily dose. For most large mammals, thetotal daily dosage is from about 0.1 milligrams to about 1000milligrams, preferably from about 0.2 milligram to about 50 milligrams.In the case of a 70 kg adult human, the total daily dose will generallybe from about 0.2 milligrams to about 200 milligrams. This dosageregimen may be adjusted to provide the optimal therapeutic response.

The invention also relates to a set (kit) consisting of separate packsof

-   a) an effective amount of a compound according to the invention or a    physiologically acceptable salt, solvate or prodrug thereof, and-   b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound according tothe invention and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilised form.

Experimental Section

Some abbreviations that may appear in this application are as follows:

Abbreviations Designation ACN acetonitrile ATP Adenosine triphosphate bBroad peak BOC tert-butyloxycarbonyl BOP-ClBis(2-oxo-3-oxazolidinyl)phosphinic chloride d Doublet DBU1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane dd doublet ofdoublets DMSO dimethylsulfoxide DIEA N,N-Diisopropylethylamine DIPEAdiisopropylethylamine DMF dimethylformamide DTT dithiothreitol EDTAEthylenediaminetetraacetic acid equiv. equivalents Et ethyl EtOAc ethylacetate h hour HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid¹H-NMR proton NMR HPLC High pressure/performance liquid chromatographyLC Liquid chromatography LC/MS Liquid chromatography coupled to massspectrometry m multiplet M Molecular ion m/z Mass-to-charge ratio MHzmegahertz Me methyl min minutes MeOH methanol MS Massspectrometry/spectrum N Normal (unit of concentration) NMO4-methylmorpholine N-oxide NMP N-methyl-2-pyrrolidone NMR NuclearMagnetic Resonance PG Protecting group psi Pounds per square inch qQuartette (or quartet) Rf Retention factor RT/rt Room temperature Rt./RTRetention time s Singlet S-Phos2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl triplet t triplet TertTertiary TEA Triethylamine TFA Trifluoroacetic acid THABTetrahexylammonium bromide THF Tetrahydrofuran T3P 1-PropanephosphonicAcid Cyclic Anhydride UV ultraviolet VIS visible x times

The compounds of the present invention can be prepared according to theprocedures of the following Schemes and Examples, using appropriatematerials and are further exemplified by the following specificexamples. Moreover, by utilizing the procedures described herein, inconjunction with ordinary skills in the art, additional compounds of thepresent invention claimed herein can be readily prepared. The compoundsillustrated in the examples are not, however, to be construed as formingthe only genus that is considered as the invention. The examples furtherillustrate details for the preparation of the compounds of the presentinvention. Those skilled in the art will readily understand that knownvariations of the conditions and processes of the following preparativeprocedures can be used to prepare these compounds.

The instant compounds are generally isolated in the form of theirpharmaceutically acceptable salts, such as those described above. Theamine-free bases corresponding to the isolated salts can be generated byneutralization with a suitable base, such as aqueous sodiumhydrogencarbonate, sodium carbonate, sodium hydroxide and potassiumhydroxide, and extraction of the liberated amine-free base into anorganic solvent, followed by evaporation. The amine-free base, isolatedin this manner, can be further converted into another pharmaceuticallyacceptable salt by dissolution in an organic solvent, followed byaddition of the appropriate acid and subsequent evaporation,precipitation or crystallization.

The invention will be illustrated, but not limited, by reference to thespecific embodiments described in the following schemes and examples.Unless otherwise indicated in the schemes, the variables have the samemeaning as described above.

Unless otherwise specified, all starting materials are obtained fromcommercially suppliers and used without further purifications. Unlessotherwise specified, all temperatures are expressed in ° C. and allreactions are conducted at room temperature. Compounds were purified byeither silica chromatography or preparative HPLC.

The present invention also relates to processes for manufacturing thecompounds of Formula (I), Formula (II), Formula (III), Formula (IV) andFormula (V), as described above, according to the hereinafter describedschemes and working examples.

Synthetic Procedures

Methods Associated with Reaction Steps in Scheme 1 and Scheme 2Method A: Nucleophilc Aromatic Substitution Using an Oxygen Nucleophile

6-(3-aminophenoxy)-5-chloropyrimidin-4-amine

Into a 20-mL microwave vial was placed 5,6-dichloropyrimidin-4-amine(500.00 mg; 3.05 mmol), cesium carbonate (1.49 g: 4.57 mmol), and3-aminophenol (499.08 mg; 4.57 mmol) suspended in DMF (12.00 ml). Thereaction mixture was run in the microwave at 160° C. for 2 hours. Thereaction mixture was allowed to cool to rt. The mixture was thenfiltered through a plug of silica gel. The solution was concentratedunder reduced pressure and then lyophilized overnight to afford6-(3-aminophenoxy)-5-chloropyrimidin-4-amine as a black solid crude.

Method B: Nucleophilic Aromatic Substitution Using a NitrogenNucelophile

tert-butyl4-{[(6-amino-5-chloropyrimidin-4-yl)amino]methyl}piperidine-1-carboxylate

Into a 10-mL vial was placed 5,6-dichloropyrimidin-4-amine (250.00 mg;1.52 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (653.40mg; 3.05 mmol), and N,N-diisopropylethylamine (1.01 ml; 6.10 mmol)suspended in NMP (2.50 ml). The reaction mixture was run in themicrowave at 150° C. for 2 hours. The reaction mixture was allowed tocool to rt. The mixture was purified using Biotage column chromatographyeluting from 50-100% EtOAc/Hexanes. Fractions containing the desiredproduct were combined and concentrated under reduced pressure to affordtert-butyl4-{[(6-amino-5-chloropyrimidin-4-yl)amino]methyl}piperidine-1-carboxylateas a yellow viscous oil.

Method C: Suzuki Coupling

6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine

Into a 20-mL microwave vial was placed6-(3-aminophenoxy)-5-chloropyrimidin-4-amine (400.00 mg; 1.69 mmol.),(4-phenoxyphenyl)boronic acid (542.62 mg; 2.54 mmol), palladium acetate(18.97 mg; 0.08 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl(69.39 mg; 0.17 mmol), potassium carbonate (700.77 mg; 5.07 mmol)suspended in dioxane (8.00 ml) and water (0.80 ml). The reaction mixturewas run in the microwave for 20 minutes at 140° C. The reaction mixturewas allowed to cool to rt. Na2SO4 was added to the mixture which wassubsequently filtered through a plug of silica gel and concentratedunder reduced pressure. The crude mixture was purified using Biotagecolumn chromatography eluting from 80-100% EtOAc/hexanes, then 0-100%MeOH/EtOAc. Fractions containing the desired product were combined andconcentrated under reduced pressure. The residue was lyophilizedovernight to afford6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine as a yellowsolid (177.00 mg, 74% yield).

Method D: Deprotection of Tert-Butyloxycarbonyl (BOC)-Protected Amine

5-(4-phenoxyphenyl)-N-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine

Into a 20-mL vial was placed tert-butyl4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidine-1-carboxylate(534.60 mg; 1.12 mmol) dissolved in methanol (4.00 ml). Hydrogenchloride (2.0 M solution in diethyl ether) (5.62 ml) was added to themixture. The reaction was stirred at rt overnight. The reaction mixturewas concentrated under reduced pressured and subsequently lyophilizedovernight to afford5-(4-phenoxyphenyl)-N-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine as ayellow solid crude.

Method E: Amide Formation from Carboxylic Acid

N-(3-{[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]oxy}phenyl)acrylamide

Into a 20 mL reaction vial was added acrylic acid (0.01 ml; 0.12 mmol),and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (42.04 mg; 0.17 mmol),and N,N-diisopropylethylamine (0.07 ml; 0.41 mmol) suspended in dioxane(3.00 ml). The reaction mixture was stirred at rt for 1 h.6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine (40.00 mg; 0.08mmol) was then added. The reaction mixture was stirred at rt overnight.The crude mixture was purified using Biotage column chromatographyeluting from 50-100% EtOAc/Hexanes, then 0-40% MeOH/EtOAc. Fractionscontaining the desired product were combined and concentrated underreduced pressure. The residue was then purified using preparative HPLCeluting from 35-45% CH₃CN in 0.1% TFA in H₂O. fractions containing thedesired product were combined and lyophilized overnight to affordN-(3-{[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]oxy}phenyl)acrylamideas a white solid (29.00 mg, 25% yield). HPLC purity: 97%, RT=4.264 min.MS: m/z=425 [M+H]⁺, RT=2.14 min. ¹H-NMR (DMSO-d₆) δ 10.14 (s, 1H), 8.00(s, 1H), 7.41 (s, 1H), 7.36-7.30 (m, 5H), 7.22 (t, 1H), 7.09 (t, 1H),7.03-7.01 (m, 4H), 6.71 (d, 1H), 6.53 (broad s, 2H), 6.34 (dd, 1H), 6.18(d, 1H), 5.69 (d, 1H).

Method F: Amide Formation from Acid Chloride in Presence of InorganicBase

N-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine

Into a 20 mL reaction vial was added5-(4-phenoxyphenyl)-N-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine(70.00 mg; 0.19 mmol), sodium bicarbonate (23.49 mg; 0.28 mmol)suspended in THF (3.00 ml) and water (0.30 ml). The mixture was cooledto 0° C. Acryloyl chloride (0.02 ml; 0.22 mm ol) was added. The ice bathwas left to melt. The reaction mixture was then stirred at rt overnight.The crude mixture was purified using Biotage column chromatographyeluting 0-50% MeOH/EtOAc. Fractions containing the desired product werecombined and concentrated under reduced pressure. The residue waslyophilized overnight to affordN-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamineas a white solid (30.00 mg, 37% yield). HPLC purity: 97%, RT=3.665 min.MS: m/z=430 [M+H]⁺, RT=1.53 min. ¹H-NMR (DMSO-d₆) δ 7.93 (s, 1H), 7.40(t, 2H), 7.21-7.08 (m, 8H), 6.76 (dd, 1H), 6.04 (d, 1H), 5.61 (d, 1H),5.43 (s, 2H), 4.34 (d, 1H), 3.98 (d, 1H), 3.12 (t, 2H), 2.95 (t, 1H),2.56 (t, 1H), 1.81 (m, 1H), 1.59 (m, 2H), 0.92 (m, 2H).

Method G: Amide Formation from Acid Chloride in Presence of Organic Base

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide

Into a 20 mL vial was placed 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline(30.00 mg, 0.08 mmol), N, N-diethylethanamine (0.02 mL, 0.17 mmol)suspended in 1-methylpyrrolidin-2-one (0.35 mL) and dichloromethane(2.00 mL). The resulting mixture was cooled to 0° C. Added acryloylchloride (0.02 mL, 0.25 mmol). The ice bath was left to melt and thereaction mixture was stirred at rt overnight. The reaction mixture waspurified using Biotage column chromatography eluting 0-40% MeOH inEtOAc. Fractions containing the desired product were combined andconcentrated. Purified using prep-HPLC eluting 25-55% CH₃CN in 0.1% TFAin H2O. Fractions containing the desired product were combined andlyophilized overnight to affordN-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide as a whitesolid (12.00 mg, 35% yield). HPLC purity: 100%, RT=4.235 min. MS:m/z=409 [M+H]⁺, RT=3.38 min. ¹H-NMR (DMSO-d₆) δ 10.23 (s, 1H), 8.52 (s,1H), 8.43 (d, 1H), 7.95 (s, 1H), 7.71 (d, 1H), 7.44-7.33 (m, 4H), 7.19(d, 2H), 7.13 (t, 1H), 7.09 (d, 2H), 7.02 (d, 2H), 6.80 (d, 1H), 6.45(dd, 1H), 6.26 (d, 1H), 5.75 (d, 1H).

Method H: Nucleophilic Aromatic Substitution Using an Aromatic Amine

N4-(3-aminophenyl)-5-chloropyrimidine-4,6-diamine

Into a 20 mL was placed 5,6-dichloropyrimidin-4-amine (500 mg, 3.05mmol), benzene-1,3-diamine (329.72 mg, 3.05 mmol) and a pre-made mixtureof TFA:TEA (1:1 mol) (347.64 mg: 308.52 mg) dissolved in DMSO (6 mL).The mixture was heated at 90° C. overnight. The reaction mixture wasthen cooled to rt and the crude mixture was purified using columnchromatography eluting 0-40% MeOH in EtOAc. The fractions containing thedesired product was concentrated and lyophilized overnight to afford thedesired product N4-(3-aminophenyl)-5-chloropyrimidine-4,6-diamine (82%yield) as a brown syrup.

Method I: Nucleophilic Aromatic Substitution Using a NitrogenNucleophile

4-(((6-amino-5-chloropyrimidin-4-yl)amino)methyl)piperidin-2-one

Into a 20 mL vial was placed 5,6-dichloropyrimidin-4-amine (100 mg, 0.61mmol), 4-(((6-amino-5-chloropyrimidin-4-yl)amino)methyl)piperidin-2-one(117.24 mg, 0.91 mmol), and DBU (0.18 mL 1.22 mmol) dissolved in DMF (2mL). The reaction mixture was stirred at 90° C. overnight. The mixturewas then cooled to rt. The crude mixture was purified using columnchromatography eluting 0-100% MeOH in EtOAc. Fractions containing thedesired product was combined and concentrated and lyophilized overnightto afford the desired product4-(((6-amino-5-chloropyrimidin-4-yl)amino)methyl)piperidin-2-one (90%yield) as a yellow solid.

Methods Associated with Reaction Steps in Scheme 3Method S1: Nucleophilic Aromatic Substitution

tert-butyl6-((6-amino-5-chloropyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate

In a round bottom flask containing 5,6-dichloro-pyrimidin-4-ylamine(300.00 mg; 1.83 mmol; 1.00 eq.) and6-amino-2-aza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester(466.02 mg; 2.20 mmol; 1.20 eq.) in NMP (1.00 ml) was added DIPEA (0.91ml; 5.49 mmol; 3.00 eq.). The reaction mixture was stirred at 155° C.for 4 h before it was concentrated.

Method S2: Suzuki Coupling

tert-butyl6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptane-2-carboxylate

In a microwave vial containing6-(6-Amino-5-chloro-pyrimidin-4-ylamino)-2-aza-spiro[3.3]heptane-2-carboxylicacid tert-butyl ester (828.00 mg; 2.44 mmol; 1.00 eq.) in dioxane (4.00ml; 46.94 mmol; 19.27 eq.) and water (0.40 ml; 22.20 mmol; 9.11 eq.) wasadded cesium carbonate (1190.86 mg; 3.65 mmol; 1.50 eq.), palladium(II)acetate (27.35 mg; 0.12 mmol; 0.05 eq.), 4-phenoxyphenylboronic acid(651.87 mg; 3.05 mmol; 1.25 eq.) and2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (100.03 mg; 0.24 mmol;0.10 eq.). The reaction mixture was stirred at 140° C. for 16 h beforeit was concentrated and separated on a 50 g silica gel column withgradient EtOAc/Hexane (0-100%). The fractions were concentrated andcarried to the next step.

Method S3: Deprotection of Tert-Butyloxycarbonyl-Protected Amine

5-(4-phenoxyphenyl)-N⁴-(2-azaspiro[3.3]heptan-6-yl)pyrimidine-4,6-diamine

In a round bottom flask containing6-[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-2-aza-spiro[3.3]heptane-2-carboxylicacid tert-butyl ester (167.23 mg; 0.35 mmol; 1.00 eq.) in methanol (5.00ml) was added hydrogen chloride (1.80 ml; 3.53 mmol; 10.00 eq.). Thereaction was stirred for 16 h before it was concentrated and carried tothe next step.

Method S3A: Deprotection of Tert-Butyloxycarbonyl-Protected Amine

5-(4-phenoxyphenyl)-N⁴-(2-azaspiro[3.3]heptan-6-yl)pyrimidine-4,6-diamine

In a round bottom flask containing6-[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-2-aza-spiro[3.3]heptane-2-carboxylicacid tert-butyl ester (167.23 mg; 0.35 mmol; 1.00 eq.) in methanol (5.00ml) was added hydrogen chloride (1.80 ml; 3.53 mmol; 10.00 eq.). Thereaction was stirred for 16 h before it was concentrated and purified byHPLC. The fractions containing the desired product were lyophilized toafford the title compound as a white solid (50.3 mg, 34%). HPLC purity:95%. MS: m/z=374[M+H]⁺. ¹H NMR (CD₃OD) δ 8.25 (s, 1H), 7.10-7.44 (m,8H), 4.60 (m, 1H), 4.20 (s, 2H), 4.01 (s, 2H), 2.69 (m, 2H), 2.32 (m,2H).

Method S4A: Amide Formation Using T3P

1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-yn-1-one

In a microwave vial containingN-(2-Aza-spiro[3.3]hept-6-yl)-5-(4-phenoxy-phenyl)-pyrimidine-4,6-diaminehydrochloride (80.00 mg; 0.20 mmol; 1.00 eq.) in DCM (1.00 ml) was addedDIPEA (0.16 ml; 0.98 mmol; 5.00 eq.) and propiolic acid (24.20 μl; 0.39mmol; 2.00 eq.) followed by2,4,6-Tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (0.12ml; 0.29 mmol; 1.50 eq.). The reaction was stirred at rt for 1 h beforeit was concentrated and purified by preparative HPLC (0.1% TFA-H₂O/ACN).Fractions containing the desired product were combined and lyophilizedovernight to afford1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-yn-1-oneas a white solid (27.8 mg, 26.1%). HPLC purity: 99%. MS: m/z=426 [M+H]⁺.¹H NMR (CD₃OD) δ 8.25 (s, 1H), 7.18-7.49 (m, 9H), 4.32 (d, 1H), 4.09 (d,2H), 3.89 (d, 1H), 2.60 (m, 2H), 2.29 (m, 2H).

Method S4B: Amide Formation Using an Acid Chloride in Pyridine

1-((1R,5S)-6-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one

To a round bottom flask containingN-[(1S,5R)-1-(3-Aza-bicyclo[3.1.0]hex-6-yl)methyl]-5-(4-phenoxy-phenyl)-pyrimidine-4,6-diaminehydrochloride (259.68 mg; 0.63 mmol; 1.00 eq.) in pyridine (1.00 ml;12.36 mmol; 19.52 eq.) was added acryloyl chloride (0.05 ml; 0.63 mmol;1.00 eq.) in DCM (3.00 ml; 46.80 mmol; 73.88 eq.) over 1 h at 0° C. Thereaction mixture was allowed to warm to room temperature and stirredovernight. It was concentrated and the crude product was subjected topreparative HPLC. Fractions containing the desired product were combinedand lyophilized overnight to afford1-((1R,5S)-6-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-oneas a white solid (2.1 mg, 0.6%). HPLC purity: 99%. MS: m/z=428[M+H]⁺. ¹HNMR (CD₃OD) δ 8.24 (s, 1H), 7.21-7.46 (m, 9H), 6.53 (m, 1H), 6.22 (m,1H), 5.74 (m, 1H), 3.77 (m, 2H), 3.69 (m, 1H), 3.41 (m, 2H), 1.70 (m,2H), 0.93 (m, 2H).

Method S4C: Amide Formation Using an Acid Chloride in THF

1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-en-1-one

To a round bottom flask containing(3S,4S)-4-{[6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-methyl}-piperidin-3-olhydrochloride (591.95 mg; 1.38 mmol; 1.00 eq.) and DIPEA (0.69 ml; 4.15mmol; 5.00 eq.) in THF (30.00 ml) was slowly added acryloyl chloride(0.11 ml; 1.38 mmol; 1.00 eq.) in 1 mL THF over 1 h. The reactionmixture was concentrated and purified with using preparative HPLC.Fractions containing the desired product were combined and lyophilizedovernight to afford1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-en-1-oneas a white solid (21.5 mg, 2.7%). HPLC purity: 99%. MS: m/z=446 [M+H]⁺.¹H NMR (CD₃OD) δ 8.25 (s, 1H), 7.10-7.45 (m, 9H), 6.73 (dd, 1H), 6.34(d, 1H), 5.77 (d, 1H), 4.5 (m, 1H), 4.03 (m, 1H), 3.62 (m, 1H), 3.50 (m,1H), 3.25 (m, 1H), 3.01 (m, 1H), 2.57 (m, 1H), 1.71 (m, 2H), 1.19 (m,1H).

Method S4D: Amide Formation Using BOP-Cl

1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-yn-1-one

To a 20 mL reaction vial was added propiolic acid (0.02 ml; 0.37 mmol;1.10 eq.), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (171.33 mg; 0.67mmol; 2.00 eq.) and ethyl-diisopropyl-amine (0.28 ml; 1.68 mmol; 5.00eq.) and 1.0 mL DMF. The reaction was stirred at rt for 1 h. Then(3S,4S)-4-{[6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-methyl}-piperidin-3-olhydrochloride (144.00 mg; 0.34 mmol; 1.00 eq.) in 1.0 mL DMF was addedto the reaction mixture. The reaction mixture was stirred at rtovernight and then concentrated. The crude product was subjected topreparative HPLC. Fractions containing the desired product were combinedand lyophilized overnight to afford1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-yn-1-oneas a white solid (35.2 mg, 18.6%). HPLC purity: 99%. MS: m/z=444 [M+H]⁺.¹H NMR (CD₃OD) δ 8.24 (s, 1H), 7.10-7.46 (m, 9H), 4.36 (m, 2H), 4.00 (d,1H), 3.74 (m, 1H), 3.52 (m, 1H), 3.25 (m, 1H), 3.00 (m, 1H), 2.64 (m,1H), 1.76 (m, 2H), 1.30 (m, 1H).

Methods Associated with Reaction Steps in Scheme 4Method AA: Nucleophilic Aromatic Substitution

(4-(6-Amino-5-chloro-pyrimidin-4-ylamino)-phenyl)-acetic acid ethylester

To a vial with stirbar were added 5,6-dichloro-pyrimidin-4-ylamine (1.4g, 8.537 mmol, 1.0 eq), (4-amino-phenyl)-acetic acid ethyl ester (4.3 g,23.993 mmol, 2.8 eq), N,N-diisopropylethylamine (4.5 ml, 25.611 mmol,3.0 eq), dissolved in n-butanol (100 ml). The reaction suspension wasflushed with nitrogen and heated to 115° C. for 8 days. The mixture wasconcentrated in vacuo, dissolved in EtOAc, washed with water (2×) andbrine (1×), dried over sodium sulfate, and concentrated in vacuo. Thecrude mixture was purified using Biotage column chromatography elutingfrom 30-70% EtOAc/hexanes. Fractions containing the desired product werecombined and concentrated under reduced pressure to afford(4-(6-amino-5-chloro-pyrimidin-4-ylamino)-phenyl)-acetic acid ethylester (1.71 g, 49% yield) as white crystals. MS: m/z=307 [M+H]⁺. ¹H-NMR(DMSO-d₆) δ 8.41 (s, 1H), 7.93 (s, 1H), 7.55 (d, 2H), 7.19 (d, 2H), 6.76(bs, 2H), 4.11 (q, 2H), 1.21 (t, 3H).

Method BB: Suzuki Coupling

(4-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-acetic acidethyl ester

Into a microwave vial was placed[4-(6-amino-5-chloro-pyrimidin-4-ylamino)-phenyl]-acetic acid ethylester (1.4 g; 3.423 mmol; 1.0 eq.), (4-phenoxyphenyl)boronic acid(1598.9 mg; 7.470 mmol; 2.18 eq.), palladium acetate (38.4 mg; 0.171mmol; 0.1 eq.), dicyclohexyl-(2′,6′-dimethoxy-biphenyl-2-yl)-phosphane(140.5 mg; 0.342 mmol; 0.1 eq.), potassium carbonate (1419.2 mg; 10.269mmol; 3.0 eq.) suspended in dioxane (15.0 ml) and water (1.5 ml). Thevial was flushed with nitrogen. The reaction vial was run in a microwavefor 3 hours at 150° C. The mixture was filtered, quenched in water andextracted with EtOAc (3×). The combined organic layer were dried oversodium sulfate, filtered and concentrated in vacuo. The crude compoundwas purified using Biotage column chromatography (50/50% Hexanes/EtOActo 100% EtOAc). Fractions containing the desired product were collectedand concentrated to afford(4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-acetic acidethyl ester (1.43 g, 90% yield) as a yellow foam. MS: m/z=441 [M+H]⁺.¹H-NMR (DMSO-d₆) δ 8.06 (s, 1H), 7.45 (t, 4H), 7.34 (d, 2H), 7.16 (dd,8H), 5.77 (bs, 2H), 4.10 (q, 2H), 3.56 (s, 2H), 1.20 (t, 3H).

Method CC: Ester Hydrolysis

(4-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-acetic acid

To a vial with stirbar were added{4-[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-aceticacid ethyl ester (1430.0 mg; 3.084 mmol; 1.0 eq.) dissolved in dioxane(15.0 ml; 176.040 mmol; 57.1 eq.), and aqueous sodium hydroxide (2 N,9.3 ml; 18.504 mmol; 6.0 eq.). The reaction mixture was stirred at roomtemperature for 1.5 h. The reaction was quenched by the addition ofwater, and washed once with EtOAc. The aqueous phase was acidified with1N hydrochloric acid. The precipitate was filtered and dried in vacuo toafford(4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-acetic acid(1.11 g, 85% yield) as white solid.

The filtrate was extracted with EtOAc (2×). The organic phase was driedover sodium sulfate, filtered and concentrated in vacuo to afford(4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-acetic acid(265 mg, 19% yield) as white solid. MS: m/z=413 [M+H]⁺. ¹H-NMR (DMSO-d₆)δ 12.20 (bs, 1H), 8.05 (s, 1H), 7.41-7-39 (m, 4H), 7.34-7.32 (d, 2H),7.16-7.11 (m, 8H).

Method DD: Weinreb Amide Synthesis

(4-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-N-methoxy-N-methyl-acetamide

To a round bottom flask with stirbar were added{4-[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-aceticacid (1375 mg; 3.2 mmol; 1 eq.), N,O-dimethylhydroxylamine hydrochloride(344.2 mg; 3.529 mmol; 1.1 eq.),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (922.5 mg;0.005 mol; 1.5 eq.), 1-hydroxybenzotriazole (HOBT) hydrate (225.4 mg;1.668 mmol; 0.5 eq.), N,N-diisopropylethylamine (0.8 ml; 4.812 mmol; 1.5eq.), dissolved in DMF (20.0 ml). The reaction mixture was stirred atroom temperature overnight.

The reaction was diluted with EtOAc, and washed with water (2×) andbrine (1×). The organic phase was dried over sodium sulfate, filteredand concentrated in vacuo. The crude compound was purified using Biotagecolumn chromatography (30-100% EtOAc/hexane). Collected fractionscontaining the desired product were concentrated. The solid wasdissolved in DCM and washed with water (3×). The organic phase was driedover sodium sulfate, filtered and concentrated in vacuo to afford(4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-N-methoxy-N-methyl-acetamide(751 mg, 51% yield) as white crystals. MS: m/z=456 [M+H]⁺, ¹H-NMR(DMSO-d₆) δ 7.92 (s, 1H), 7.44 (m, 4H), 7.40 (d, 2H), 7.26 (d, 2H), 7.14(t, 5H), 6.11 (t, 1H), 5.50 (bs, 2H), 4.52 (d, 2H), 3.50 (s, 3H), 3.23(s, 3H).

Method EE: Weinreb Ketone Synthesis Using 1-Propenylmagnesium Bromide

1-(4-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-pent-3-en-2-one

In a round bottom flask with stirbar was added2-{4-[6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-methoxy-N-methyl-acetamide(275.0 mg; 0.604 mmol; 1.0 eq.), suspended in THF (2.5 ml; 12.343 mmol;20.4 eq.). The suspension was cooled to 0° C. At this temperature wasadded 1-prop enylmagnesium bromide (12.1 ml; 6.037 mmol; 10.0 eq.) dropby drop at constant temperature. After complete addition, the reactionmixture was stirred 30 min at room temperature.

The reaction suspension was quenched with aqueous solution of ammoniumchloride, and extracted with EtOAc (3×). The combined organic phase weredried over sodium sulfate, filtered and concentrated in vacuo. The crudewas dissolved in DMSO and purified by preparative HPLC to afford1-(4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-pent-3-en-2-one(78 mg, 19%). MS: m/z=437 [M+H]⁺. ¹H-NMR (DMSO-d₆) 8.50 (bs, 1H), 8.29(s, 1H), 7.46 (t, 2H), 7.39 (d, 2H), 7.27 (d, 2H), 7.21 (m, 6H), 7.09(bs, 1H), 7.02 (dd, 1H), 6.20 (ss, 1H), 3.86 (s, 3H), 1.89 (d, 3H).

Method FF: Weinreb Ketone Synthesis Using 1-Propynylmagnesium Bromide

1-(4-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-pent-3-yn-2-one

In a round bottom flask with stirbar was added2-{4-[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-N-methoxy-N-methyl-acetamide(275.0 mg; 0.604 mmol; 1.0 eq.), suspended in THF (2.5 ml; 30.857 mmol;51.1 eq.). The suspension was cooled to 0° C. At this temperature wasadded 1-pro pynylmagnesium bromide (12.1 ml; 6.037 mmol; 10.0 eq.) dropby drop at constant temperature to afford a red solution. After completeaddition, the reaction mixture was stirred 30 min at room temperature.The reaction suspension was quenched with aqueous solution of ammoniumchloride, and extracted with EtOAc (3×). The combined organic phase weredried over sodium sulfate, filtered and concentrated in vacuo. The crudecompound was dissolved in DMSO and purified by preparative HPLC toafford1-(4-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-pent-3-yn-2-one(68 mg, 17% yield) as light yellow solid. MS: m/z=435 [M+H]⁺. ¹H-NMR(DMSO-d₆) □δ 8.43 (bs, 1H), 8.28 (s, 1H), 7.46 (t, 2H), 7.42 (d, 2h),7.37 (d, 2H), 7.31-7.13 (m, 7H), 6.99 (bs, 2H), 3.87 (s, 2H), 2.04 (s,3H).

Method GG: Weinreb Ketone Synthesis Using Vinylmagnesium Bromide

1-(3-((Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-propenone

In a round bottom flask with stirbar was added3-{[6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-methyl}-N-methoxy-N-methyl-benzamide(140.0 mg; 0.307 mmol; 1.0 eq.), dissolved in THF (2.0 ml; 24.686 mmol;80.3 eq.). The suspension was cooled to 0° C. At this temperature wasadded vinylmagnesium bromide 1.0M solution in THF (3.1 ml; 3.073 mmol;10.0 eq.) drop by drop at constant temperature. After complete addition,the reaction mixture was stirred 30 min at room temperature. Thereaction suspension was quenched with aqueous solution of ammoniumchloride, and extracted with EtOAc (3×). The combined organic phase weredried over sodium sulfate, filtered and concentrated in vacuo. The crudecompound was dissolved in DMSO and purified by preparative HPLC toafford1-(3-((amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-propenone(20 mg, 10% yield) as white amorphous solid. MS: m/z=484 [M+H]⁺. ¹H-NMR(DMSO-d₆) δ 8.34 (s, 1H), 7.86 (t, 2H), 7.64 (t, 1H), 7.52 (m, 4H), 7.35(d, 2H), 7.23 (dd, 3H), 7.14 (d, 2H), 7.02 (bs, 2H), 4.65 (d, 2H), 3.21(t, 2H), 2.96 (t, 2H).

Analytical Methodology

Analytical LC/MS was Performed Using the Following Three Methods:

Method 1:

A Discovery C¹⁸, 5 μm, 3×30 mm column was used at a flow rate of 400μL/min, sample loop 5 μL, mobile phase: (A) water with 0.1% formic acid,mobile phase, (B) methanol with 0.1% formic acid; retention times aregiven in minutes. Method details: (I) runs on a Quaternary Pump G1311A(Agilent) with UV/VIS diode array detector G1315B (Agilent) and FinniganLCQ Duo MS detector in ESI+modus with UV-detection at 254 and 280 nmwith a gradient of 15-95% (B) in a 3.2 min linear gradient (II) hold for1.4 min at 95% (B) (III) decrease from 95-15% (B) in a 0.1 min lineargradient (IV) hold for 2.3 min at 15% (B).

Method 2:

A Waters Symmetry C¹⁸, 3.5 μm, 4.6×75 mm column at a flow rate of 1mL/min, sample loop 10 μL, mobile phase (A) is water with 0.05% TFA,mobile phase (B) is ACN with 0.05% TFA; retention times are given inminutes. Methods details: (I) runs on a Binary Pump G1312A (Agilent)with UV/Vis diode array detector G1315B (Agilent) and Agilent G1956B(SL) MS detector in ESI+mode with UV-detection at 254 and 280 nm with agradient of 20-85% (B) in a 10 min linear gradient (II) hold for 1 minat 85% (B) (III) decrease from 20-85% (B) in a 0.2 min linear gradient(IV) hold for 3.8 min at 20% (B).

Method 3:

Gradient: 4.2 min/Flow: 2 ml/min 99:01-0:100 Water+0.1% (Vol.) TFA;Acetonitril+0.1% (Vol.) TFA; 0.0 to 0.2 min: 99:01; 0.2 to 3.8 min:99:01→0:100; 3.8 to 4.2 min: 0:100; Column: Chromolith PerformanceRP18e; 100 mm long, 3 mm diameter; Wavelength: 220 nm.

HPLC Method for Purity Determination

Purity was determined on an Agilent HPLC using UV detection at 254 nmwith a Waters Xbridge C8 column (5 μm, 4.6×50 mm). Mobile Phase A: 0.1%TFA in water. Mobile phase B: 0.1% TFA in acetonitrile. The methodinvolved a gradient from 98% mobile phase A/2% mobile phase B to 100%mobile phase B over 8 minutes at a flow rate of 2 mL/min.

General Method for Preparative HPLC

Preparative HPLC was carried out on a Waters preparative HPLC systemusing a Waters Sunfire C18 column (5 or 10 μm). Mobile phase A: waterwith 0.1% TFA. Mobile phase B: acetonitrile. Crude compounds were loadedon the column using a minimum volume of methanol or DMSO. A typicalgradient used for separation was 0-50% Mobile Phase B over 20-25 minuteswith an optional wash step (100% Mobile Phase B).

EXAMPLES

The working examples presented below are intended to illustrateparticular embodiments of the invention, and are not intended to limitthe scope of the specification or the claims in any way. In this sectionexperimental details are provided for a number of Example compoundsaccording to Formula (I), Formula (II), Formula (III), Formula (IV) andFormula (V).

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one(A1)

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl3-aminopyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, andacryloyl chloride using methods B, C, D and F. HPLC purity: 100%. MS:m/z=402 [M+H]⁺.

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one(A2)

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl3-hydroxypiperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, andacryloyl chloride using methods A, C, D, and F. HPLC purity: 100%. MS:m/z=417 [M+H]⁺.

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)phenyl)acrylamide(A3)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, benzene-1,3-diamine,(4-phenoxyphenyl)boronic acid, and acryloyl chloride using methods H, C,and F. HPLC purity: 100%. MS: m/z=424 [M+H]⁺. ¹H-NMR (DMSO-d₆), δ 10.11(s, 1H), 8.47 (broad s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.31-6.97 (m,14H), 6.37 (dd, 1H), 6.19 (d, 1H), 5.69 (d, 1H).

(R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one(A4)

(R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl3-(aminomethyl)pyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and acryloyl chloride using methods B, C, D, and F. HPLC purity: 100%.MS: m/z=416 [M+H]⁺.

N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)acrylamide(A5)

N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl(pyrrolidin-3-ylmethyl)carbamate, (4-phenoxyphenyl)boronic acid, andacryloyl chloride using methods B, C, D, and F. HPLC purity 97%. MS:m/z=416 [M+H]⁺.

1-(4-(((5-(4-phenoxyphenyl)pyrimidinyl)-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-one(A6)

1-(4-(((5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5-bromo-4-chloropyrimidine, tert-butyl4-(hydroxymethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronicacid, and acryloyl chloride using methods A, C, D, and F. HPLC purity:92%. MS: m/z=416 [M+H]⁺.

N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)acrylamide(A7)

N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl(piperidin-4-ylmethyl)carbamate, (4-phenoxyphenyl)boronic acid, andacryloyl chloride using method B, C, D, and F. HPLC purity: 100%. MS:m/z=430 [M+H]⁺.

4-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidine-1-carbonyl)-1-methylpyridin-2(1H)-one(A8)

4-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidine-1-carbonyl)-1-methylpyridin-2(1H)-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid using methodsB, C, D, and E. HPLC purity: 100%. MS: m/z=511 [M+H]⁺. ¹H-NMR (DMSO-d₆)δ 8.28 (s, 1H), 7.69 (d, 1H), 7.38 (t, 2H), 7.20 (d, 2H), 7.14-6.90 (m,8H), 6.19 (s, 1H), 6.06 (d, 1H), 1.28 (d, 1H), 3.47 (d, 1H), 3.35 (s,3H), 3.18 (s, 2H), 2.90 (t, 1H), 2.61 (t, 1H), 1.76 (s, 1H), 1.58 (d,1H), 1.48 (d, 1H), 1.04-0.92 (m, 2H).

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)but-2-yn-1-one(A9)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)but-2-yn-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(hydroxymethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronicacid, and but-2-ynoic acid using methods A, C, D, and E. HPLC purity:100%. MS: m/z=443 [M+H]⁺.

5-(4-phenoxyphenyl)-N4-((1-(vinylsulfonyl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine(A10)

5-(4-phenoxyphenyl)-N4-((1-(vinylsulfonyl)piperidin-4-yl)methyl)pyrimidine-4,6-diaminewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acidand 2-chloroethanesulfonyl chloride using methods B, C, D and G. HPLCpurity: 89%. MS: m/z=466 [M+H]⁺.

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-((2-methoxyethyl)(methyl)amino)but-2-en-1-one(A11)

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-((2-methoxyethyl)(methyl)amino)but-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acidand (E)-4-((2-methoxyethyl)(methyl)amino)but-2-enoic acid using methodsB, C, D, and E. HPLC purity: 99%. MS: m/z=531 [M+H]⁺.

(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(2-fluoropyridin-3-yl)methanone(A12)

(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(2-fluoropyridin-3-yl)methanonewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and 2-fluoronicotinic acid using methods B, C, D, and E. HPLC purity:100%. MS: m/z=499 [M+H]⁺. ¹H-NMR (DMSO-d₆) δ 8.28 (s, 1H), 8.25 (d, 1H),7.92 (t, 1H), 7.39-7.36 (m, 3H), 7.20-6.90 (m, 10H), 4.39 (d, 1H), 3.28(d, 1H), 3.19 (m, 2H), 2.94 (t, 1H), 2.70 (t, 1H), 1.78 (s, 1H), 1.63(d, 1H), 1.49 (d, 1H), 1.05-0.92 (m, 2H).

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2-en-1-one(A13)

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and (E)-but-2-enoic acid using methods B, C, D, and E. HPLC purity:100%. MS: m/z=444 [M+H]⁺. ¹H-NMR (DMSO-d₆) δ 8.27 (s, 1H), 7.38 (t, 2H),7.21-6.88 (m, 10H), 6.60-6.52 (m, 1H), 6.40 (d, 1H), 4.27 (m, 1H), 3.96(m, 1H), 3.16 (m, 3H), 2.87 (m, 1H), 1.75 (d, 4H), 1.53 (m, 2H), 0.88(m, 2H).

N4-((1-(cyclopropylsulfonyl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine(A14)

N4-((1-(cyclopropylsulfonyl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diaminewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and cyclopropanesulfonyl chloride using methods B, C, D, and G. HPLCpurity: 96%. MS: m/z=480 [M+H]⁺.

(Z)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2-en-1-one(A15)

(Z)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and but-2-ynoic acid using methods B, C, D, E, and hydrogenation usingLindlar's catalyst. HPLC purity: 81%. MS: m/z=444 [M+H]⁺. ¹H-NMR(DMSO-d₆) δ 8.35 (s, 1H), 7.45 (t, 2H), 7.28-6.95 (m, 10H), 6.06 (d,1H), 5.94-5.86 (m, 1H), 4.35 (d, 1H), 3.83 (d, 1H), 3.24 (m, 2H), 2.94(t, 1H), 2.55 (t, 1H), 1.82-1.74 (m, 4H), 1.61 (d, 2H), 0.96 (m, 2H).

1-(4-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)piperidin-1-yl)prop-2-en-1-one(A16)

1-(4-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(2-aminoethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and acryloyl chloride using methods B, C, D, and F. HPLC purity: 98%.MS: m/z=444 [M+H]⁺.

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-one(A17)

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl3-(hydroxymethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronicacid, and acryloyl chloride using methods A, C, D, and F. HPLC purity:100%. MS: m/z=431 [M+H]⁺.

N-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)acrylamide(A18)

N-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl(2-aminoethyl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloylchloride using methods B, C, D, and F. HPLC purity: 100%. MS: m/z=376[M+H]⁺.

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one(A19)

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl3-hydroxypyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, andacryloyl chloride using methods A, C, D, and F. HPLC purity: 100%. MS:m/z=403 [M+H]⁺.

N-(1-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)cyclopentyl)acrylamide(A20)

N-(1-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)cyclopentyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl(1-(aminomethyl)cyclopentyl)carbamate, (4-phenoxyphenyl)boronic acid,and acryloyl chloride using methods B, C, D, and F. HPLC purity: 99%.MS: m/z=430 [M+H]⁺.

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one(A21)

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronicacid, and acryloyl chloride using methods A, C, D, and F. HPLC purity:100%. MS: m/z=417 [M+H]⁺.

1-(4-(((5-fluoro-3-(4-phenoxyphenyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A22)

1-(4-(((5-fluoro-3-(4-phenoxyphenyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 3-bromo-2-chloro-5-fluoropyridine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and acryloyl chloride using methods B, C, D, and F. HPLC purity: 99%.MS: m/z=432 [M+H]⁺. ¹H-NMR (DMSO-d₆) δ 8.01 (s, 1H), 7.47-7.45 (m, 4H),7.32 (d, 1H), 7.21 (t, 1H), 7.12-7.09 (m, 4H), 6.82-6.75 (m, 1H), 6.07(d, 1H), 5.82 (broad s, 1H), 5.64 (d, 1H), 4.39 (d, 1H), 4.02 (d, 1H),3.18 (d, 2H), 2.99 (t, 1H), 2.59 (t, 1H), 1.92 (s, 1H), 1.68 (m, 2H),1.00 (m, 2H).

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)ethanone(A23)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)ethanonewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and acetic acid using methods B, C, D, and E. HPLC purity: 100%. MS:m/z=418 [M+H]⁺. ¹H-NMR (DMSO-d₆) δ 8.36 (s, 1H), 7.46 (t, 2H), 7.29-7.01(m, 10H), 4.32 (d, 1H), 3.78 (d, 1H), 3.24 (m, 2H), 2.94 (t, 1H), 2.46(t, 1H), 1.97 (s, 3H), 1.79 (s, 1H), 1.58 (t, 2H), 1.07-0.87 (m, 2H).

(E)-7-(3-(4-(4-((3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)amino)-4-oxobut-2-en-1-yl)piperazin-1-yl)-3-oxopropyl)-5,5-difluoro-1,3-dimethyl-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uide(A24)

(E)-7-(3-(4-(4-((3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)amino)-4-oxobut-2-en-1-yl)piperazin-1-yl)-3-oxopropyl)-5,5-difluoro-1,3-dimethyl-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,(4-phenoxyphenyl)boronic acid,(E)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)but-2-enoic acid, and7-(2-carboxyethyl)-5,5-difluoro-1,3-dimethyl-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uideusing methods A, B, E, D, and E. HPLC purity: 100%. MS: m/z=797 [M+H]⁺.

1-(4-(((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A25)

1-(4-(((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5-bromo-4-chloropyrimidin-2-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and acryloyl chloride using methods B, C, D, and F. HPLC purity: 100%.MS: m/z=430 [M+H]⁺.

(S)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one(A26)

(S)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, (S)-tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate, 4-phenoxyphenyl)boronicacid, and acryloyl chloride using methods A, C, D, and F. HPLC purity:100%. MS: m/z=417 [M+H]⁺.

N-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)ethyl)acrylamide(A27)

N-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)ethyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl(2-hydroxyethyl)carbamate, 4-phenoxyphenyl)boronic acid, and acryloylchloride using methods A, C, D, and F. HPLC purity: 100%. MS: m/z=377[M+H]⁺. ¹H-NMR (DMSO-d₆) δ 8.28 (s, 1H), 8.14 (t, 1H), 7.43 (t, 2H),7.31 (d, 2H), 7.18 (t, 1H), 7.11 (d, 2H), 7.01 (d, 2H), 6.71 (broad s,1.5H), 6.16 (dd, 1H), 6.07 (d, 1H), 5.57 (d, 1H), 4.34 (t, 2H), 3.42 (q,2H).

(S)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one(A28)

(S)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, (S)-tert-butyl3-(aminomethyl)pyrrolidine-1-carboxylate, 4-phenoxyphenyl)boronic acid,and acryloyl chloride using methods B, C, D, and F. HPLC purity: 98%.MS: m/z=416 [M+H]⁺.

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2-methylprop-2-en-1-one(A29)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2-methylprop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and methacrylic acid using methods B, C, D, and E. HPLC purity: 100%.MS: m/z=444 [M+H]⁺.

(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclohex-1-en-1-yl)methanone(A30)

(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclohex-1-en-1-yl)methanonewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and cyclohex-1-enecarboxylic acid using methods B, C, D, and E. HPLCpurity: 100%. MS: m/z=484 [M+H]⁺.

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-3-methylbut-2-en-1-one(A31)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-3-methylbut-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and 3-methylbut-2-enoyl chloride using methods B, C, D, and F. HPLCpurity: 100%. MS: m/z=458 [M+H]⁺.

(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclopent-1-en-1-yl)methanone(A32)

(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclopent-1-en-1-yl)methanonewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and cyclopent-1-enecarboxylic acid using methods B, C, D, and E. HPLCpurity: 99%. MS: m/z=470 [M+H]⁺.

1-(4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A33)

1-(4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,(1-benzyl-1H-pyrazol-4-yl)boronic acid, and acryloyl chloride usingmethods B, C, D, and F. HPLC purity: 100%. MS: m/z=418 [M+H]⁺.

1-(4-(((6-amino-5-(4-(3-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A34)

1-(4-(((6-amino-5-(4-(3-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,(4-(3-fluorophenoxy)phenyl)boronic acid, and acryloyl chloride usingmethods B, C, D, and E. HPLC purity: 100%. MS: m/z=448 [M+H]⁺.

(E)-7-(3-((2-(4-(4-((3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)amino)-4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)amino)-3-oxopropyl)-5,5-difluoro-1,3-dimethyl-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uide(A35)

(E)-7-(3-((2-(4-(4-((3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)amino)-4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)amino)-3-oxopropyl)-5,5-difluoro-1,3-dimethyl-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,(4-(3-fluorophenoxy)phenyl)boronic acid,(E)-4-(4-(2-((tert-butoxycarbonyl)amino)ethyl)piperazin-1-yl)but-2-enoicacid, and7-(2-carboxyethyl)-5,5-difluoro-1,3-dimethyl-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uideusing methods A, C, E, D, and E. HPLC purity: 100%. MS: m/z=840 [M+H]⁺.

1-(4-(((6-amino-2-methyl-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A36)

1-(4-(((6-amino-2-methyl-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloro-2-methylpyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and acryloyl chloride using methods B, C, D, and F. HPLC purity: 100%.MS: m/z=444 [M+H]⁺.

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)prop-2-en-1-one(A37)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate,(4-phenoxyphenyl)boronic acid, and acryloyl chloride using methods B, C,D, and F. HPLC purity: 100%. MS: m/z=446 [M+H]⁺.

(R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one(A38)

(R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronicacid, and acryloyl chloride using methods A, C, D, and F. HPLC purity:96%. MS: m/z=417 [M+H]⁺.

1-(4-(((6-amino-5-(4-(phenylamino)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A39)

1-(4-(((6-amino-5-(4-(phenylamino)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,N-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, andacryloyl chloride using methods B, C, D, and F. HPLC purity: 98%. MS:m/z=429 [M+H]⁺.

1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-1H-pyrrol-2(5H)-one(A40)

1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-1H-pyrrol-2(5H)-onewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,(4-phenoxyphenyl)boronic acid, and 2,5-dimethoxy-2,5-dihydrofuran usingmethods A, C. HPLC purity: 93%. MS: m/z=437 [M+H]⁺.

1-(4-(((6-amino-5-(4-benzylphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one (A41)

1-(4-(((6-amino-5-(4-benzylphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1l-carboxylate,2-(4-benzylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and acryloylchloride using methods B, C, D, and F. HPLC purity: 100%. MS: m/z=428[M+H]⁺.

(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclobut-1-en-1-yl)methanone(A42)

(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclobut-1-en-1-yl)methanonewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and cyclobut-1-enecarboxylic acid using methods B, C, D, and E. HPLCpurity: 99%. MS: m/z=456 [M+H]⁺.

(Z)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)but-2-en-1-one(A43)

(Z)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)but-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(hydroxymethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronicacid, and but-2-ynoic acid using methods A, C, D, E, and hydrogenationusing Lindlar's catalyst. HPLC purity: 100%. MS: m/z=445 [M+H]⁺.

1-(4-(((6-amino-2-methyl-5-(4-phenoxyphenyl)pyrimidin-4-yl)(methyl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A44)

1-(4-(((6-amino-2-methyl-5-(4-phenoxyphenyl)pyrimidin-4-yl)(methyl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloro-2-methylpyrimidin-4-amine, tert-butyl4-((methylamino)methyl)piperidine-1-carboxylate,(4-phenoxyphenyl)boronic acid, and acryloyl chloride using methods B, C,D, and F. HPLC purity: 100%. MS: m/z=458 [M+H]⁺.

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2-chloroethanone(A45)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2-chloroethanonewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and 2-chloroacetyl chloride using methods B, C, D, and G. HPLC purity:100%. MS: m/z=452 [M+H]⁺.

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-yn-1-one(A46)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-yn-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and propiolic acid using methods B, C, D, and E. HPLC purity: 98%. MS:m/z=428 [M+H]⁺.

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)(methyl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A47)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)(methyl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-((methylamino)methyl)piperidine-1-carboxylate,(4-phenoxyphenyl)boronic acid, and acryloyl chloride using methods B, C,D, and F. HPLC purity: 100%. MS: m/z=444 [M+H]⁺. ¹H-NMR (DMSO-d₆) δ 8.32(s, 1H), 7.45 (t, 2H), 7.33 (d, 2H), 7.20 (t, 1H), 7.12 (t, 4H), 6.95(broad s, 1.5H), 6.77 (dd, 1H), 6.07 (d, 1H), 5.65 (d, 1H), 4.38 (d,1H), 4.01 (d, 1H), 3.36 (m, 2H), 2.99 (t, 1H), 2.68 (s, 3H), 2.57 (t,1H), 1.92 (s, 1H), 1.50 (d, 2H), 0.97 (t, 2H).

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one(A48)

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl3-(aminomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate,(4-phenoxyphenyl)boronic acid, and acryloyl chloride using methods B, C,D, and F. HPLC purity: 100%. MS: m/z=456 [M+H]⁺.

N-((1S,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclopentyl)acrylamide(A49)

N-((1S,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclopentyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine,tert-butyl-trans-3-aminocyclopentyl)carbamate, (4-phenoxyphenyl)boronicacid, and acryloyl chloride using methods B, C, D, and F. HPLC purity:100%. MS: m/z=416 [M+H]⁺. ¹H-NMR (DMSO-d₆) δ 8.35 (s, 1H), 8.12 (d, 1H),7.46 (t, 2H), 7.28-7.15 (m, 7H), 6.92 (broad s, 1.5H), 6.81 (d, 1H),6.20 (dd, 1H), 6.06 (d, 1H), 5.57 (d, 1H), 4.64 (s, 1H), 4.21 (q, 1H),2.05-1.91 (m, 2H), 1.86-1.71 (m, 2H), 1.55-1.34 (m, 2H).

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)butyl)acrylamide(A50)

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)butyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl(4-aminobutyl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloylchloride using methods B, C, D, and F. HPLC purity: 100%. MS: m/z=404[M+H]⁺.

N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide(A51)

N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl(trans-3-aminocyclohexyl)carbamate, (4-phenoxyphenyl)boronic acid, andacryloyl chloride using methods B, C, D, and F. HPLC purity: 100%. MS:m/z=431 [M+H]⁺.

1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)azepan-1-yl)prop-2-en-1-one(A52)

1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)azepan-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl3-aminoazepane-1-carboxylate, (4-phenoxyphenyl)boronic acid, andacryloyl chloride using methods B, C, D, and F. HPLC purity: 100%. MS:m/z=430 [M+H]⁺.

N-(trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide(A53)

N-(trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl(cis-3-aminocyclohexyl)carbamate, (4-phenoxyphenyl)boronic acid, andacryloyl chloride using methods B, C, D, and F. HPLC purity: 100%. MS:m/z=430 [M+H]⁺.

(E)-5-(4-phenoxyphenyl)-N4-((1-(styrylsulfonyl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine(A54)

(E)-5-(4-phenoxyphenyl)-N4-((1-(styrylsulfonyl)piperidin-4-yl)methyl)pyrimidine-4,6-diaminewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and (E)-2-phenylethenesulfonyl chloride using methods B, C, D, G. HPLCpurity: 98%. MS: m/z=542 [M+H]⁺.

N4-((1-(methylsulfonyl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine(A55)

N4-((1-(methylsulfonyl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diaminewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and methanesulfonyl chloride using methods B, C, D, and G. HPLC purity:99%. MS: m/z=454 [M+H]⁺.

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2,3-dihydroxypropan-1-one(A56)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2,3-dihydroxypropan-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,acryloyl chloride using methods B, C, D, F, and dihydroxylation usingosmium tetraoxide. HPLC purity: 96%. MS: m/z=464 [M+H]⁺.

4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-2-one(A57)

4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-2-onewas prepared from 5,6-dichloropyrimidin-4-amine,4-(aminomethyl)piperidin-2-one, (4-phenoxyphenyl)boronic acid usingmethods I, and C. HPLC purity: 100%. MS: m/z=390 [M+H]⁺.

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)ethenesulfonamide(A58)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)ethenesulfonamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,(4-phenoxyphenyl)boronic acid, and 2-chloroethanesulfonyl chloride usingmethods A, C, and G. HPLC purity: 77%. MS: m/z=461 [M+H]⁺.

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)propyl)acrylamide(A59)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)propyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl(3-aminopropyl)carbamate, (4-phenoxyphenyl)boronic acid, and acryloylchloride using methods B, C, D, and F. HPLC purity: 100%. MS: m/z=390[M+H]⁺.

N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)pyridin-3-yl)acrylamide(A60)

N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)pyridin-3-yl)acrylamidewas prepared from 6-dichloropyrimidin-4-amine, 5-aminopyridin-3-ol,(4-phenoxyphenyl)boronic acid, and acryloyl chloride using methods A, C,and F. HPLC purity: 97%. MS: m/z=426 [M+H]⁺. ¹H-NMR (DMSO-d₆) δ 10.49(s, 1H), 8.58 (s, 1H), 8.13-8.09 (m, 2H), 7.97 (s, 1H), 7.46-7.40 (m,4H), 7.17 (t, 1H), 7.12-7.09 (m, 4H), 6.64 (broad s, 1.2H), 6.43 (dd,1H), 6.30 (d, 1H), 5.83 (d, 1H).

(R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-yn-1-one(A61)

(R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-yn-1-onewas prepared from 6-dichloropyrimidin-4-amine, (R)-tert-butyl3-(aminomethyl)pyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and propiolic acid using methods B, C, D and E. HPLC purity: 99%. MS:m/z=414 [M+H]⁺.

(R,E)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-one(A62)

(R,E)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-onewas prepared from 6-dichloropyrimidin-4-amine, (R)-tert-butyl3-(aminomethyl)pyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and (E)-4-(dimethylamino)but-2-enoic acid using methods B, C, D, and E.HPLC purity: 100%. MS: m/z=473 [M+H]⁺.

(E)-N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)-4-(dimethylamino)but-2-enamide(A63)

(E)-N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)-4-(dimethylamino)but-2-enamidewas prepared from 6-dichloropyrimidin-4-amine, tert-butyl(cis-3-aminocyclohexyl)carbamate, (4-phenoxyphenyl)boronic acid, and(E)-4-(dimethylamino)but-2-enoic acid using methods B, C, D, and E. HPLCpurity: 99%. MS: m/z=487 [M+H]⁺.

N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)propiolamide(A64)

N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)propiolamidewas prepared from 6-dichloropyrimidin-4-amine, tert-butyl(cis-3-aminocyclohexyl)carbamate, (4-phenoxyphenyl)boronic acid, andpropiolic acid using methods B, C, D, and E. HPLC purity: 100%. MS:m/z=428 [M+H]⁺.

(S)-1-(2-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-one(A65)

(S)-1-(2-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-onewas prepared from 6-dichloropyrimidin-4-amine, (S)-tert-butyl2-(hydroxymethyl)morpholine-4-carboxylate, (4-phenoxyphenyl)boronicacid, and acryloyl chloride using methods A, C, D, and F. HPLC purity:99%. MS: m/z=433 [M+H]⁺.

(R)-1-(2-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-one(A66)

(R)-1-(2-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-onewas prepared from 6-dichloropyrimidin-4-amine, (R)-tert-butyl2-(hydroxymethyl)morpholine-4-carboxylate, (4-phenoxyphenyl)boronicacid, and acryloyl chloride using methods A, C, D, and F. HPLC purity:100%. MS: m/z=433 [M+H]⁺.

N-(3-((6-amino-5-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A67)

N-(3-((6-amino-5-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and acryloyl chloride using methods A, C, and F. HPLC purity: 100%. MS:m/z=431 [M+H]⁺. ¹H-NMR (DMSO-d₆) δ 10.21 (s, 1H), 8.16 (s, 1H), 8.03 (s,1H), 7.74 (s, 1H), 7.51 (s, 1H), 7.42, 7.30 (m, 3H), 7.15-7.09 (m, 3H),7.03-6.61 (m, 2.5H), 6.42 (dd, 1H), 6.25 (d, 1H), 5.57 (d, 1H), 5.40 (s,2H).

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-yn-1-one(A68)

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-yn-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl3-(aminomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate,(4-phenoxyphenyl)boronic acid, and propiolic acid using methods B, C, D,and E. HPLC purity: 96%. MS: m/z=454 [M+H]⁺.

N-(3-((6-amino-5-(1-(4-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A69)

N-(3-((6-amino-5-(1-(4-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)benzonitrile,and acryloyl chloride using methods A, C, and F. HPLC purity: 97%. MS:m/z=438 [M+H]⁺. ¹H-NMR (DMSO-d₆) δ 10.21 (s, 1H), 8.18 (s, 1H), 8.03 (s,1H), 7.82 (d, 2H), 7.76 (s, 1H), 7.52 (s, 1H), 7.42 (d, 2H), 7.40 (d,1H), 7.30 (t, 1H), 6.89-6.67 (m, 2.5H), 6.42 (dd, 1H), 6.25 (d, 1H),5.77 (d, 1H), 5.49 (s, 2H).

N-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)acrylamide(A70)

N-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, benzene-1,3-diamine,1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and acryloyl chloride using methods H, C, and F. HPLC purity: 99%. MS:m/z=412 [M+H]⁺. ¹H-NMR (DMSO-d₆) δ 10.17 (s, 1H), 8.65 (s, 1H), 8.26 (s,1H), 8.02 (s, 1H), 7.78 (s, 1H), 7.61 (s, 1H), 7.44-7.03 (m, 10H), 6.45(dd, 1H), 6.26 (d, 1H), 5.76 (d, 1H), 5.39 (s, 2H).

(E)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)-4-(dimethylamino)but-2-en-1-one(A71)

(E)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)-4-(dimethylamino)but-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl3-(aminomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate,(4-phenoxyphenyl)boronic acid, and (E)-4-(dimethylamino)but-2-enoic acidusing methods B, C, D, and E. HPLC purity: 100%. MS: m/z=513 [M+H]⁺.

N-(3-((6-amino-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A72)

N-(3-((6-amino-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and acryloyl chloride using methods A, C, and F. HPLC purity: 99%. MS:m/z=443 [M+H]⁺. ¹H-NMR (DMSO-d₆) δ 10.21 (s, 1H), 8.08 (s, 1H), 8.01 (s,1H), 7.70 (s, 1H), 7.50 (s, 1H), 7.41 (d, 1H), 7.33-7.26 (m, 3H), 6.90(d, 2H), 6.83-6.58 (m, 2.5H), 6.40 (dd, 1H), 6.25 (d, 1H), 5.76 (d, 1H),5.28 (s, 2H), 3.73 (s, 3H).

(R,E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-one(A73)

(R,E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl3-aminopyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and(E)-4-(dimethylamino)but-2-enoic acid using methods B, C, D and E. HPLCpurity: 99%. MS: m/z=459 [M+H]⁺.

(R,E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one(A74)

(R,E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl3-aminopiperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and(E)-4-(dimethylamino)but-2-enoic acid using methods B, C, D and E. HPLCpurity: 100%. MS: m/z=473 [M+H]⁺.

1-(trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-4-hydroxypyrrolidin-1-yl)prop-2-en-1-one(A75)

1-(trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-4-hydroxypyrrolidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, trans-tert-butyl3-amino-4-hydroxypyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronicacid, and acryloyl chloride using methods B, C, D, and F. HPLC purity:100%. MS: m/z=418 [M+H]⁺.

1-(4-(((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A76)

1-(4-(((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 3,4-dichloropyridin-2-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and acryloyl chloride using methods B, C, D, and F. HPLC purity: 100%.MS: m/z=429 [M+H]⁺.

1-(4-(((6-amino-5-(4-fluorophenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A77)

1-(4-(((6-amino-5-(4-fluorophenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-fluorophenyl)boronic acid,and acryloyl chloride in four steps according to general scheme 2, usingmethods I, C, D and G. MS: m/z=356 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ8.35 (s, 1H), 7.40 (t, 2H), 7.32 (dd, 2H), 7.07 (t, 1H), 6.95 (s, 2H),6.78 (dd, 1H), 6.07 (dd, 1H), 5.65 (dd, 1H), 4.37 (d, 2H), 4.01 (d, 2H),3.21 (t, 2H), 2.98 (t, 1H), 2.67-2.53 (m, 1H), 1.82 (s, 1H), 1.61 (d,2H), 0.98 (d, 2H).

1-(4-(((6-amino-5-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A78)

1-(4-(((6-amino-5-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,(4-(trifluoromethoxy)phenyl)boronic acid, and acryloyl chloride in foursteps according to general scheme 2, using methods I, C, D, and G. MS:m/z=422 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.36 (s, 1H), 7.53 (d, 2H),7.41 (d, 2H), 7.12 (t, 1H), 6.99 (s, 2H), 6.78 (dd, 1H), 6.07 (dd, 1H),5.65 (dd, 1H), 4.37 (d, 1H), 4.02 (d, 2H), 3.22 (t, 2H), 2.98 (t, 1H),2.58 (t, 1H), 1.82 (s, 1H), 1.62 (d, 2H), 0.97 (s, 2H).

1-(4-(((6-amino-5-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A79)

1-(4-(((6-amino-5-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,(4-(4-(trifluoromethyl)phenoxy)phenyl)boronic acid, and acryloylchloride in four steps according to general scheme 2, using methods I,C, D, and G. MS: m/z=498 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.37 (s,1H), 7.79 (d, 2H), 7.31 (m, 4H), 7.10 (bs, 1H), 7.01 (bs, 1H), 6.78 (dd,1H), 6.07 (dd, 1H), 5.65 (dd, 1H), 4.38 (d, 1H), 4.02 (d, 1H), 3.25 (t,2H), 3.09-2.90 (m, 1H), 2.59 (t, 1H), 1.84 (m, 1H), 1.63 (d, 2H), 0.99(m, 2H).

1-(4-(((6-amino-5-(4-(4-(fluorophenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A80)

1-(4-(((6-amino-5-(4-(4-(fluorophenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,(4-(4-fluorophenoxy)phenyl)boronic acid, and acryloyl chloride in foursteps according to general scheme 2, using methods I, C, D and G. MS:m/z=448 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.35 (s, 1H), 7.37-7.24 (m,4H), 7.22-7.11 (m, 4H), 7.05 (t, 1H), 6.92 (bs, 2H), 6.78 (dd, 1H), 6.07(dd, 1H), 5.65 (dd, 1H), 4.37 (d, 1H), 4.02 (d, 1H), 3.23 (t, 2H), 3.00(t, 1H), 2.58 (t, 1H), 1.83 (m, 1H), 1.62 (d, 2H), 0.97 (m, 2H).

1-(4-(((6-amino-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A81)

1-(4-(((6-amino-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,(4-(trifluoromethyl)phenyl)boronic acid, and acryloyl chloride in foursteps according to general scheme 2, using methods I, C, D and G. MS:m/z=406 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.36 (s, 1H), 7.92 (d, 2H),7.51 (d, 2H), 7.13 (t, 1H), 6.99 (s, 2H), 6.78 (dd, 1H), 6.07 (dd, 1H),5.65 (dd, 1H), 4.37 (d, 1H), 4.01 (d, 1H), 3.26-3.16 (m, 3H), 3.04-2.91(m, 1H), 2.65-2.53 (m, 1H), 1.83 (m, H), 1.62 (d, 2H), 1.09-0.86 (m,2H).

1-(4-(((6-amino-5-(3,4-dimethoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A82)

1-(4-(((6-amino-5-(3,4-dimethoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (3,4-dimethoxyphenyl)boronicacid, and acryloyl chloride in four steps according to general scheme 2,using methods I, C, D and G. MS: m/z=398 [M+H]⁺. ¹H-NMR (400 MHz, CD₃OD)δ 8.24 (s, 1H), 7.19 (d, 1H), 6.90 (dd, Hz, 2H), 6.76 (dd, 1H), 6.18(dd, 1H), 5.73 (dd, 1H), 4.54 (d, 1H), 4.12 (d, 1H), 3.92 (s, 3H), 3.87(s, 3H), 3.38 (bs, 2H), 3.10 (t, 1H), 2.71 (t, 1H), 2.04-1.85 (m, 1H),1.75 (bs, 2H), 1.29 (s, 1H), 1.13 (bs, 2H).

1-(4-(((6-amino-5-(3,4,5-trimethoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A83)

1-(4-(((6-amino-5-(3,4,5-trimethoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (3,4,5-trimethoxyphenyl)boronicacid, and acryloyl chloride in four steps according to general scheme 2,using methods I, C, D and G. MS: m/z=428 [M+H]⁺. ¹H-NMR (400 MHz,DMSO-d₆): δ 8.34 (s, 1H), 7.17 (s, 1H), 6.99 (s, 2H), 6.79 (dd, 1H),6.57 (s, 2H), 6.07 (dd, 1H), 5.65 (dd, 1H), 4.37 (d, 1H), 4.02 (d, 1H),3.79 (s, 6H), 3.76 (s, 3H), 3.25 (bs, 2H), 2.99 (t, 1H), 2.59 (t, 1H),1.85 (bs, 1H), 1.65 (d, 2H), 1.09-0.90 (m, 2H).

1-(4-(((6-amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A84)

1-(4-(((6-amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid, and acryloyl chloridein four steps according to general scheme 2, using methods I, C, D andG. MS: m/z=396 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.33 (s, 1H), 7.07(d, 1H), 7.04 (d, 1H), 6.93 (s, 2H), 6.83-6.73 (m, 2H), 6.70 (dd, 1H),6.07 (dd, 1H), 5.65 (dd, 1H), 4.36 (d, 1H), 4.30 (s, 3H), 4.01 (d, 1H),3.22 (s, 3H), 2.98 (t, 1H), 2.66-2.53 (m, 1H), 1.83 (m, 1H), 1.61 (d,2H), 1.10-0.83 (m, 2H).

1-(4-(((6-amino-5-(4-methoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A85)

1-(4-(((6-amino-5-(4-methoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-methoxyphenyl)boronic acid,and acryloyl chloride in four steps according to general scheme 2, usingmethods I, C, D and G. MS: m/z=368 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ8.34 (s, 1H), 7.17 (dd, 4H), 6.99 (s, 1H), 6.84 (s, 1H), 6.78 (dd, 1H),6.07 (dd, 1H), 5.65 (dd, 1H), 4.37 (d, 1H), 4.01 (d, 1H), 3.83 (s, 3H),3.22 (t, 2H), 2.98 (t, 1H), 2.58 (t, 1H), 1.82 (bs, 1H), 1.60 (d, 2H),1.07-0.86 (m, 2H).

4-(4-(4-(((1-acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile(A86)

4-(4-(4-(((1-acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrilewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-cyanophenyl)boronic acid,and acryloyl chloride in four steps according to general scheme 2, usingmethods I, C, D and G. MS: m/z=455 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ8.27 (s, 1H), 7.77 (d, 2H), 7.48-7.20 (m, 5H), 6.76 (dd, 1H), 6.18 (dd,1H), 5.73 (dd, 1H), 4.56 (d, 1H), 4.13 (d, 1H), 3.40 (d, 2H), 3.18-3.00(m, 2H), 2.79-2.63 (m, 1H), 1.96 (bs, 2H), 1.84-1.68 (m, 2H), 1.51 (d,2H), 1.25-1.04 (m, 2H).

1-(4-(((6-amino-5-(2,5-difluoro-4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A87)

1-(4-(((6-amino-5-(2,5-difluoro-4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,(2,5-difluoro-4-phenoxyphenyl)boronic acid, and acryloyl chloride infour steps according to general scheme 2, using methods I, C, D and G.MS: m/z=466 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.38 (s, 1H), 7.44 (dt,4H), 7.36-7.12 (m, 5H), 6.79 (dd, 1H), 6.07 (dd, 1H), 5.64 (dd, 1H),4.38 (d, 1H), 4.03 (d, 1H), 3.31 (bs, 1H), 3.21 (bs, 1H), 2.99 (t, 1H),2.58 (t, 1H), 1.84 (bs, 1H), 1.64 (d, 2H), 1.00 (bs, 2H).

1-(4-(((6-amino-5-(2,3-difluoro-4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A88)

1-(4-(((6-amino-5-(2,3-difluoro-4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,(2,3-difluoro-4-phenoxyphenyl)boronic acid, and acryloyl chloride infour steps according to general scheme 2, using methods I, C, D and G.MS: m/z=466 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.36 (s, 1H), 7.47 (t,J=8.0 Hz, 2H), 7.35 (bs, 1H), 7.27-7.05 (m, 5H), 6.79 (dd, 1H), 6.07(dd, 1H), 5.65 (dd, 1H), 4.38 (d, 1H), 4.02 (d, 1H), 3.25 (s, 2H),3.05-2.92 (t, 1H), 2.60 (t, 1H), 1.84 (bs, 1H), 1.61 (bs, 2H), 1.00 (bs,2H).

1-(4-(((6-amino-5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A89)

1-(4-(((6-amino-5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,(4-((1-methylpiperidin-4-yl)oxy)phenyl)boronic acid, and acryloylchloride in four steps according to general scheme 2, using methods I,C, D and G. MS: m/z=451 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.79 (s,1H), 8.35 (s, 1H), 7.19 (m, 5H), 6.93 (m, 3H), 6.78 (dd, 1H), 6.07 (dd,1H), 5.65 (dd, 1H), 4.81 (s, 1H), 4.60 (s, 1H), 4.37 (d, 1H), 4.01 (d,1H), 3.19 (d, 5H), 2.98 (t, 1H), 2.85 (d, 4H), 2.65-2.53 (m, 1H), 2.29(d, 1H), 2.06 (d, 2H), 1.81 (d, 2H), 1.59 (s, 2H), 1.33-1.16 (m, 1H),1.06-0.82 (m, 2H).

1-(4-(((6-amino-5-(4-phenoxy-2-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A90)

1-(4-(((6-amino-5-(4-phenoxy-2-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,(4-phenoxy-2-(trifluoromethyl)phenyl)boronic acid, and acryloyl chloridein four steps according to general scheme 2, using methods I, C, D andG. MS: m/z=498 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.35 (s, 1H), 7.50(dd, 2H), 7.39 (m, 2H), 7.28 (t, 1H), 7.19 (d, J=7.8 Hz, 2H), 7.16-7.07(m, 1H), 7.00 (bs, 1H), 6.78 (dd, 1H), 6.06 (dd, 1H), 5.64 (dd, 1H),4.36 (d, 1H), 4.01 (d, 1H), 3.16 (m, 2H), 2.97 (t, 1H), 2.65-2.54 (t,1H), 1.78 (bs, 1H), 1.58 (bs, 2H), 0.97 (bs, 2H).

1-(2-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)prop-2-en-1-one(A91)

1-(2-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl2,7-diazaspiro[3.5]nonane-7-carboxylate, (4-phenoxyphenyl)boronic acid,and acryloyl chloride in four steps according to general scheme 2, usingmethods I, C, D and G. MS: m/z=442 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ8.31 (s, 1H), 7.43 (t, 2H), 7.34 (d, 2H), 7.18 (t, 1H), 7.11 (d, 4H),7.04 (bs, 1H), 6.77 (dd, 1H), 6.06 (dd, 1H), 5.65 (dd, 1H), 3.10-3.90(m, 8H), 1.59 (s, 4H).

1-(8-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)prop-2-en-1-one(A92)

1-(8-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl2,8-diazaspiro[4.5]decane-2-carboxylate, (4-phenoxyphenyl)boronic acid,and acryloyl chloride in four steps according to general scheme 2, usingmethods I, C, D and G. MS: m/z=456 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ8.33 (s, 1H), 7.44 (t, 2H), 7.35 (t, 2H), 7.19 (t, 1H), 7.10 (d, 3H),6.91 (bs, 2H), 6.53 (m, 1H), 6.13 (d, 1H), 5.72-5.60 (m, 1H), 3.70-3.10(m, 11H), 1.85 (t, 1H), 1.76 (m, 2H).

1-(7-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)prop-2-en-1-one(A93)

1-(7-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl2,7-diazaspiro[4.4]nonane-2-carboxylate, (4-phenoxyphenyl)boronic acid,and acryloyl chloride in four steps according to general scheme 2, usingmethods I, C, D and G. MS: m/z=442 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ8.33 (s, 1H), 7.43 (t, 2H), 7.35 (d, 2H), 7.18 (m, 3H), 7.10 (d, 2H),6.97 (bs, 2H), 6.54 (ddd, 1H), 6.11 (d, 1H), 5.71-5.60 (m, 1H),3.70-3.10 (m, 6H), 1.77 (t, 1H), 1.68 (t, 1H), 1.39 (bs, 4H).

1-(4-(((6-amino-5-(4-(4-hydroxyphenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A94)

1-(4-(((6-amino-5-(4-(4-hydroxyphenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,(4-(4-hydroxyphenoxy)phenyl)boronic acid, and acryloyl chloride in foursteps according to general scheme 2, using methods I, C, D and G. MS:m/z=446 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.39 (bs, 1H), 8.31 (s, 1H),7.54 (t, 1H), 7.06 (dd, 2H), 7.00 (d, 2H), 6.94 (d, 1H), 6.89 (bs, 1H),6.79 (d, 2H), 6.72 (bs, 1H), 6.08 (dd, 1H), 5.66 (dd, 1H), 4.38 (d, 1H),4.01 (d, J 1H), 3.21 (d, 2H), 2.97 (t, 1H), 2.63-2.54 (m, 1H), 1.81 (bs,1H), 1.58 (d, 2H), 0.96 (bs, 2H).

1-(4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A95)

1-(4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,(4-(3-(trifluoromethyl)phenoxy)phenyl)boronic acid, and acryloylchloride in four steps according to general scheme 2, using methods I,C, D and G. MS: m/z=498 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.36 (s,1H), 7.68 (t, 1H), 7.55 (d, 1H), 7.50-7.39 (m, 2H), 7.29 (dd, 4H), 7.08(bs, 1H), 6.93 (bs, 2H), 6.78 (dd, 1H), 6.07 (dd, 1H), 5.64 (dd, 1H),4.37 (d, 1H), 4.01 (d, 1H), 3.24 (t, 2H), 3.06-2.91 (m, 1H), 2.60 (t,1H), 1.83 (bs, 1H), 1.62 (d, 2H), 0.98 (m, 2H).

1-(4-(((6-amino-5-(4-(pyridin-3-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A96)

1-(4-(((6-amino-5-(4-(pyridin-3-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,(4-(pyridin-3-yloxy)phenyl)boronic acid, and acryloyl chloride in foursteps according to general scheme 2, using methods I, C, D and G. MS:m/z=431 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.99 (d, 1H), 8.68 (d, 1H),8.39 (d, 1H), 7.69 (d, 1H), 7.49 (m, 2H), 7.42 (s, 2H), 7.34 (d, 1H),7.08 (bs, 2H), 6.78 (dd, J=16.6, 10.5 Hz, 1H), 6.07 (dd, J=16.7, 2.3 Hz,1H), 5.65 (dd, 1H), 4.70 (t, 1H), 4.38 (d, 1H), 4.02 (d, 1H), 3.26 (t,2H), 3.09-2.92 (m, 2H), 2.59 (t, 1H), 1.84 (bs, 2H), 1.64 (d, 2H), 0.99(m, 2H).

1-(4-(((6-amino-5-(4-(pyridin-4-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A97)

1-(4-(((6-amino-5-(4-(pyridin-4-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,(4-(pyridin-4-yloxy)phenyl)boronic acid, and acryloyl chloride in foursteps according to general scheme 2, using methods I, C, D and G. MS:m/z=431 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.90 (d, 1H),8.39 (s, 1H), 8.18 (m, 2H), 7.55-7.36 (m, 4H), 7.03 (s, 2H), 6.78 (dd,1H), 6.07 (dd, 1H), 5.65 (dd, 1H), 4.85 (t, 2H), 4.38 (d, 1H), 4.02 (d,1H), 3.25 (t, 2H), 3.14 (t, 2H), 3.06-2.94 (m, 2H), 2.65-2.54 (m, 1H),1.84 (bs, 1H), 1.62 (d, 2H), 1.00 (m, 2H).

1-(4-(((6-amino-5-(4-(p-tolyloxy)phenyl)pyrimidin-4-yl)meth-4-yl)amino)meth)piperidin-1-yl)prop-2-en-1-one(A98)

1-(4-(((6-amino-5-(4-(p-tolyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-(p-tolyloxy)phenyl)boronicacid, and acryloyl chloride in four steps according to general scheme 2,using methods I, C, D, G. MS: m/z=444 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆)δ 8.35 (s, 1H), 7.25 (m, 4H), 7.12 (d, 2H), 7.07 (bs, 1H), 7.04 (t, 2H),6.93 (bs, 1H), 6.78 (dd, 1H), 6.07 (dd, 1H), 5.64 (dd, 1H), 4.37 (d,1H), 4.01 (d, 1H), 3.23 (t, 2H), 2.98 (t, 1H), 2.57 (t, 1H), 2.33 (s,3H), 1.83 (bs, 1H), 1.62 (d, 2H), 0.98 (m, 2H).

1-(4-(((6-amino-5-(4-(cyclohexyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A99)

1-(4-(((6-amino-5-(4-(cyclohexyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,(4-(cyclohexyloxy)phenyl)boronic acid, and acryloyl chloride in foursteps according to general scheme 2, using methods I, C, D and G. MS:m/z=436 [M+H]⁺. ¹H-NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 1H), 7.13 (dd, 4H),7.00 (t, 1H), 6.95-6.83 (bs, 2H), 6.78 (dd, 1H), 6.07 (d, 1H), 5.64 (d,1H), 4.38 (bs, 2H), 4.01 (d, 1H), 3.22 (t, 2H), 2.98 (t, 1H), 2.58 (t,1H), 1.97 (bs, 2H), 1.91-1.67 (m, 3H), 1.67-1.21 (m, 8H), 1.07-0.86 (m,2H).

Example Compounds According to Formula (I) Synthesized Using Scheme 3and Methods S1-S4D

N⁴-((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-ylmethyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diaminehydrochloride (A100)

N⁴-((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-ylmethyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diaminehydrochloride was prepared from 5,6-dichloropyrimidin-4-amine,exo-3-Boc-6-aminomethyl-3-azabicyclo[3,1,0]hexane, and (4-phenoxyphenyl)boronic acid according to general scheme 3 using methods S1, S2, and S3.

(3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-3-olhydrochloride (A101)

(3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-3-olhydrochloride was prepared from 5,6-dichloropyrimidin-4-amine,(3S,4S)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate,and (4-phenoxyphenyl) boronic acid according to general scheme 3 usingmethods S1, S2, and S3.

(E)-1-(6-((6-amino-5-chloropyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(dimethylamino)but-2-en-1-one(A102)

(E)-1-(6-((6-amino-5-chloropyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(dimethylamino)but-2-en-1-onewas prepared 5,6-dichloropyrimidin-4-amine, tert-butyl6-amino-2-azaspiro[3.3]heptane-2-carboxylate and(E)-4-(dimethylamino)but-2-enoic acid hydrochloride in three stepsaccording to general scheme 3 using methods S1, S3, and S4A. HPLCpurity: 99%. MS: m/z=352 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.03 (s, 1H), 6.71 (m,1H), 6.47 (t, 1H), 5.23 (m, 1H), 4.41 (d, 2H), 4.16 (d, 2H), 3.96 (m,2H), 2.91 (m, 6H), 2.81 (m, 2H), 2.42 (m, 2H).

1-(3-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)azetidin-1-yl)prop-2-en-1-one(A103)

1-(3-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)azetidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl3-(2-aminoethyl)azetidine-1-carboxylate, (4-phenoxyphenyl) boronic acidand acrylic acid according to general scheme 3 using methods S1, S2, S3and S4A. HPLC purity: 99%. MS: m/z=416 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.27 (s,1H), 7.12-7.45 (m, 9H), 6.25 (m, 2H), 5.73 (d, 1H), 4.37 (t, 1H), 4.12(dd, 1H), 2.94 (dd, 1H), 3.71 (dd, 1H), 3.49 (t, 2H), 2.69 (m, 1H), 1.88(m, 2H).

1-(3-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)azetidin-1-yl)prop-2-yn-1-one(A104)

1-(3-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)azetidin-1-yl)prop-2-yn-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl3-(2-aminoethyl)azetidine-1-carboxylate, (4-phenoxyphenyl) boronic acidand propiolic acid according to general scheme 3 using methods S1, S2,S3 and S4A. HPLC purity: 99%. MS: m/z=414[M+H]⁺. ¹H NMR (CD₃OD) δ 8.27(s, 1H), 7.14-7.45 (m, 9H), 4.33 (t, 1H), 4.09 (dd, 1H), 3.91 (m, 2H),3.68 (dd, 1H), 3.49 (t, 2H), 2.69 (m, 1H), 1.87 (m, 2H).

(E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(dimethylamino)but-2-en-1-one(A105)

(E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(dimethylamino)but-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl6-hydroxyl-2-azaspiro[3.3]heptane-2-carboxylate, (4-phenoxyphenyl)boronic acid and (E)-4-(dimethylamino)but-2-enoic acid hydrochlorideaccording to general scheme 3 using methods S1, S2, S3, and S4A. HPLCpurity: 99%. MS: m/z=486 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.28 (s, 1H),7.18-7.45 (m, 9H), 6.63 (m, 1H), 6.45 (dd, 1H), 5.25 (m, 1H), 4.32 (d,2H), 4.13 (d, 2H), 4.92 (t, 2H), 3.81 (m, 6H), 2.74 (m, 2H), 2.23 (m,2H).

1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one(A106)

1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl6-hydroxyl-2-azaspiro[3.3]heptane-2-carboxylate,(1-benzyl-1H-pyrazol-4-yl)boronic acid and acrylic acid according togeneral scheme 3 using methods S1, S2, S3, and S4A. HPLC purity: 95%.MS: m/z=417 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.32 (s, 1H), 7.94 (s, 1H), 7.76(s, 1H), 7.35 (m, 5H), 6.29 (m, 2H), 5.72 (m, 1H), 5.43 (s, 2H), 5.29(m, 1H), 4.34 (d, 2H), 4.10 (d, 2H), 2.77 (m, 2H), 2.34 (m, 2H).

1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one(A107)

1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl6-amino-2-azaspiro[3.3]heptane-2-carboxylate,(1-benzyl-1H-pyrazol-4-yl)boronic acid and acrylic acid according togeneral scheme 3 using methods S1, S2, S3, and S4A. HPLC purity: 98%.MS: m/z=416 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.21 (s, 1H), 7.84 (s, 1H), 7.58(s, 1H), 7.41 (m, 5H), 6.29 (m, 2H), 5.72 (m, 1H), 5.43 (s, 2H), 4.56(s, 1H), 4.34 (d, 2H), 4.10 (d, 2H), 2.58 (m, 2H), 2.27 (m, 2H).

1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)but-2-yn-1-one(A108)

1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)but-2-yn-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl6-amino-2-azaspiro[3.3]heptane-2-carboxylate, (4-phenoxyphenyl) boronicacid and but-2-ynoic acid according to general scheme 3 using methodsS1, S2, S3, and S4A. HPLC purity: 99%. MS: m/z=440 [M+H]⁺. ¹H NMR(CD₃OD) δ 8.24 (s, 1H), 7.16-7.45 (m, 9H), 4.57 (s, 1H), 4.27 (d, 2H),4.05 (d, 2H), 2.61 (m, 2H), 2.27 (m, 2H), 2.00 (m, 3H).

1-((3S,4S)-4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-en-1-one(A109)

1-((3S,4S)-4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, (3S,4S)-tert-butyl4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate,(1-benzyl-1H-pyrazol-4-yl)boronic acid and acrylic acid according togeneral scheme 3 using methods S1, S2, S3, and S4A. HPLC purity: 99%.MS: m/z=434 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.22 (s, 1H), 7.84 (s, 1H), 7.60(s, 1H), 7.40 (m, 5H), 6.76 (m, 1H), 6.21 (d, 1H), 5.74 (d, 1H), 5.43(s, 2H), 4.53 (m, 1H), 4.08 (m, 1H), 3.61 (m, 2H), 3.03 (m, 1H), 2.72(m, 1H), 1.89 (m, 1H), 1.72 (m, 2H), 1.21 (m, 1H), 1.01 (m, 1H).

1-((3S,4S)-4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-yn-1-one(A110)

1-((3S,4S)-4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-yn-1-onewas prepared from 5,6-dichloropyrimidin-4-amine,(1-benzyl-1H-pyrazol-4-yl)boronic acid, (3S,4S)-tert-butyl4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate and propiolic acidaccording to general scheme 3 using methods S1, S2, S3, and S4A. HPLCpurity: 99%. MS: m/z=432 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.22 (s, 1H), 7.84 (s,1H), 7.69 (s, 1H), 7.40 (m, 5H), 4.43 (m, 2H), 4.01 (d, 1H), 3.62 (m,1H), 3.61 (m, 1H), 3.29 (m, 1H), 3.03 (m, 1H), 2.60 (m, 1H), 1.76 (m,3H), 1.24 (m, 1H), 1.21 (m, 1H).

1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-yn-1-one(A111)

1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-yn-1-onewas prepared from 5,6-dichloropyrimidin-4-amine,(1-benzyl-1H-pyrazol-4-yl)boronic acid, tert-butyl6-amino-2-azaspiro[3.3]heptane-2-carboxylate and propiolic acidaccording to general scheme 3 using methods S1, S2, S3, and S4A. HPLCpurity: 95%. MS: m/z=414 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.21 (s, 1H), 7.83 (s,1H), 7.57 (s, 1H), 7.41 (m, 5H), 5.42 (s, 2H), 4.54 (s, 1H), 4.31 (d,2H), 4.08 (d, 2H), 3.88 (d, 1H), 2.61 (m, 2H), 2.30 (m, 2H).

1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-yn-1-one(A112)

1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-yn-1-onewas prepared from 5,6-dichloropyrimidin-4-amine,(1-benzyl-1H-pyrazol-4-yl)boronic acid, tert-butyl6-hydroxyl-2-azaspiro[3.3]heptane-2-carboxylate and propiolic acidaccording to general scheme 3 using methods S1, S2, S3, and S4A. HPLCpurity: 95%. MS: m/z=415 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.26 (s, 1H), 7.94 (s,1H), 7.74 (s, 1H), 7.35 (m, 5H), 5.42 (s, 2H), 5.22 (m, 1H), 4.31 (d,2H), 4.08 (d, 2H), 3.88 (d, 1H), 2.76 (m, 2H), 2.39 (m, 2H).

1-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]octan-6-yl)prop-2-en-1-one(A113)

1-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]octan-6-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl2-amino-6-azaspiro[3.4]octane-6-carboxylate, (4-phenoxyphenyl) boronicacid and acrylic acid according to general scheme 3 using methods S1,S2, S3 and S4A. HPLC purity: 99%. MS: m/z=442 [M+H]⁺. ¹H NMR (CD₃OD) δ8.25 (s, 1H), 7.16-7.47 (m, 9H), 6.50 (m, 1H), 6.24 (m, 1H), 5.73 (m,1H), 4.71 (m, 1H), 3.60 (t, 1H), 3.52 (m, 2H), 3.41 (s, 1H), 2.34 (m,1H), 2.11 (m, 3H), 1.97 (m, 1H).

1-(6-((6-amino-5-(4-(pyridin-4-yloxy)phenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one(A114)

1-(6-((6-amino-5-(4-(pyridin-4-yloxy)phenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl6-hydroxyl-2-azaspiro[3.3]heptane-2-carboxylate,(4-(pyridin-4-yloxy)phenyl)boronic acid and acrylic acid according togeneral scheme 3 using methods S1, S2, S3, and S4A. HPLC purity: 99%.MS: m/z=430 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.75 (m, 2H), 8.31 (m, 1H), 7.56(m, 4H), 7.44 (m, 2H), 6.27 (m, 1H), 5.73 (m, 1H), 5.24 (m, 1H), 4.26(d, 2H), 4.01 (d, 2H), 2.73 (m, 2H), 2.25 (m, 2H).

1-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]octan-6-yl)prop-2-yn-1-one(A115)

1-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]octan-6-yl)prop-2-yn-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl2-amino-6-azaspiro[3.4]octane-6-carboxylate, (4-phenoxyphenyl) boronicacid and propiolic acid according to general scheme 3 using methods S1,S2, S3, and S4A. HPLC purity: 99%. MS: m/z=440 [M+H]⁺. ¹H NMR (CD₃OD) δ8.01 (s, 1H), 7.12-7.48 (m, 9H), 4.52 (t, 1H), 3.71 (t, 1H), 3.58 (s,1H), 3.50 (dd, 1H), 2.33 (m, 2H), 2.05 (m, 2H), 1.96 (m, 2H), 1.47 (s,2H).

1-(6-((6-amino-5-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one(A116)

1-(6-((6-amino-5-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl6-amino-2-azaspiro[3.3]heptane-2-carboxylate,(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)boronic acid and acrylic acidaccording to general scheme 3 using methods S1, S2, S3, and S4A. HPLCpurity: 99%. MS: m/z=416 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.77 (m, 2H), 8.23 (s,1H), 8.00 (s, 1H), 7.88 (m, 2H), 7.68 (s, 1H), 6.26 (m, 2H), 5.75 (m,3H), 4.54 (m, 1H), 4.27 (d, 2H), 4.11 (d, 2H), 2.59 (m, 2H), 2.26 (m,2H).

N-(1,3-trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide(A117)

N-(1,3-trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butylcis-3-aminocyclobutyl carbamate, (4-phenoxyphenyl) boronic acid andacrylic acid according to scheme 3 using methods S1, S2, S3, and S4A.HPLC purity: 99%. MS: m/z=402 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.25 (s, 1H),7.10-7.46 (m, 9H), 6.26 (m, 2H), 5.63 (d, 1H), 4.77 (m, 1H), 4.24 (m,1H), 2.42 (m, 2H), 2.27 (m, 2H).

N-((1,3-cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide(A118)

N-((1,3-cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyltrans-3-aminocyclobutyl carbamate, (4-phenoxyphenyl) boronic acid andacrylic acid according to general scheme 3 using methods S1, S2, S3, andS4A. HPLC purity 99%. MS: m/=402 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.23 (s, 1H),7.10-7.46 (m, 9H), 6.26 (m, 2H), 5.60 (d, 1H), 4.31 (m, 1H), 4.03 (m,1H), 2.76 (m, 2H), 1.98 (m, 2H).

N⁴-(2-((2-chloroethyl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine(A119)

N⁴-(2-((2-chloroethyl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine(10.5 mg, 11.2%) was prepared from 5,6-dichloropyrimidin-4-amine,6-aino-2-aza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester,(4-phenoxyphenyl)boronic acid and 2-chloro-ethanesulfonyl chlorideaccording to general scheme 3 using methods S1, S2, S3, and S4C. HPLCpurity 95%. MS: m/z=501 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.24 (s, 1H), 7.10-7.47(m, 9H), 6.70 (m, 1H), 6.19 (d, 1H), 6.01 (d, 1H), 4.62 (m, 1H), 3.58(s, 2H), 3.13 (s, 2H), 2.37 (m, 2H), 1.81 (m, 2H).

1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one (A120)

1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine,6-hydroxyl-2-aza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester,(4-phenoxyphenyl) boronic acid and acryloyl chloride according togeneral scheme 3 using methods S1, S2, S3, and S4C. HPLC purity: 99%.MS: m/z=429 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.36 (s, 1H), 7.09-7.45 (m, 9H),6.25 (m, 2H), 5.74 (m, 1H), 5.28 (m, 1H), 4.33 (d, 2H), 4.09 (d, 2H),2.74 (m, 2H), 2.32 (m, 2H).

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-methoxypiperidin-1-yl)prop-2-en-1-one(A121)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-methoxypiperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine,4-aminomethyl-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester,(4-phenoxyphenyl) boronic acid and acryloyl chloride according togeneral scheme 3 using with method S1, S2, S3, and S4C. HPLC purity:99%. MS: m/z=460 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.28 (s, 1H), 7.13-7.43 (m,9H), 6.77 (m, 1H), 6.17 (d, 1H), 5.75 (d, 1H), 4.27 (d, 1H), 3.85 (d,1H), 3.62 (s, 2H), 3.83 (m, 1H), 3.22 (s, 3H), 3.04 (m, 1H), 1.79 (m,2H), 1.44 (m, 2H).

N-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl)acrylamide(A122)

N-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl(6-aminospiro[3.3]heptan-2-yl)carbamate, (4-phenoxyphenyl) boronic acidand acryloyl chloride according to general scheme 3 using methods S1,S2, S3, and S4C. HPLC purity: 95%. MS: m/z=442 [M+H]⁺. ¹H NMR (CD₃OD) δ8.23 (s, 1H), 7.10-7.46 (m, 9H), 6.23 (m, 1H), 5.66 (m, 1H), 4.59 (m,1H), 3.69 (m, 1H), 3.19 (d, 1H), 2.54 (m, 2H), 2.08-2.34 (m, 6H).

1-(1-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-7-azaspiro[3.5]nonan-7-yl)prop-2-en-1-one(A123)

1-(1-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-7-azaspiro[3.5]nonan-7-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl1-amino-7-azaspiro[3.5]nonane-7-carboxylate, (4-phenoxyphenyl) boronicacid and acryloyl chloride according to general scheme 3 using methodsS1, S2, S3, and S4C. HPLC purity: 99%. MS: m/z=456 [M+H]⁺. ¹H NMR(CD₃OD) δ 8.24 (s, 1H), 7.11-7.50 (m, 9H), 6.73 (m, 1H), 6.18 (d, 1H),5.71 (d, 1H), 4.53 (m, 1H), 4.21 (m, 1H), 3.83 (m, 1H), 3.18 (m, 1H),2.95 (m, 1H), 2.27 (m, 2H), 2.06 (m, 1H), 1.86 (m, 2H), 1.68 (m, 3H),1.37 (m, 1H).

1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one(A124)

1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl6-amino-2-azaspiro[3.3]heptane-2-carboxylate, (4-phenoxyphenyl) boronicacid and acryloyl chloride according to general scheme 3 using methodsS1, S2, S3, and S4C. HPLC purity: 99%. MS: m/z=428 [M+H]⁺. ¹H NMR(CD₃OD) δ 8.24 (s, 1H), 7.13-7.50 (m, 9H), 6.25 (m, 2H), 5.71 (m, 1H),4.59 (m, 1H), 4.35 (d, 2H), 4.11 (d, 2H), 2.61 (m, 2H), 2.29 (m, 2H).

1-(8-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-azaspiro[3.5]nonan-5-yl)prop-2-en-1-one(A125)

1-(8-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-azaspiro[3.5]nonan-5-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl8-amino-5-azaspiro[3.5]nonane-5-carboxylate, (4-phenoxyphenyl) boronicacid and acryloyl chloride according to general scheme 3 using methodsS1, S2, S3, and S4C. HPLC purity: 95%. MS: m/z=456 [M+H]⁺. ¹H NMR(CD₃OD) δ 8.28 (s, 1H), 7.15-7.43 (m, 9H), 6.61 (m, 1H), 6.13 (d, 1H),5.67 (d, 1H), 4.64 (m, 1H), 3.95 (m, 1H), 3.03 (m, 1H), 2.66 (m, 1H),2.30 (m, 1H), 2.19 (m, 2H), 2.07 (m, 1H), 1.80 (m, 4H), 1.30 (m, 1H).

(E)-1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-4-(dimethylamino)but-2-en-1-one(A126)

(E)-1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-4-(dimethylamino)but-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, (3S,4S)-tert-butyl4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid and (E)-4-(dimethylamino)but-2-enoic acid hydrochlorideaccording to general scheme 3 using methods S1, S2, S3, and S4D. HPLCpurity: 99%. MS: m/z=503 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.26 (s, 1H),7.10-7.45 (m, 9H), 6.91 (d, 1H), 6.67 (m, 1H), 4.54 (m, 1H), 4.02 (m,1H), 3.97 (m, 2H), 3.74 (m, 1H), 3.51 (m, 1H), 3.00 (m, 1H), 2.62 (m,1H), 1.76 (m, 2H), 1.23 (m, 1H).

(E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)-4-(dimethylamino)but-2-en-1-one(A127)

(E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)-4-(dimethylamino)but-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl6-amino-2-azaspiro[3.3]heptane-2-carboxylate, (4-phenoxyphenyl) boronicacid and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride accordingto general scheme 3 using methods S1, S2, S3, and S4D. HPLC purity: 99%.MS: m/z=485 [M+H]⁺. ¹H NMR (CD₃OD) δ 8.24 (s, 1H), 7.13-7.50 (m, 9H),6.75 (m, 1H), 6.46 (dd, 1H), 4.59 (m, 1H), 4.35 (d, 2H), 4.11 (d, 2H),3.91 (m, 2H), 2.82 (d, 6H), 2.61 (m, 2H), 2.29 (m, 2H).

Example Compounds According to Formula (I) Synthesized Using Scheme 4and Methods AA-GG

3-((6-Amino-5-chloro-pyrimidin-4-ylamino)-methyl)-benzoic acid methylester (A128)

3-((6-Amino-5-chloro-pyrimidin-4-ylamino)-methyl)-benzoic acid methylester was prepared from 3-aminomethyl-benzoic acid methyl ester usingMethod AA (59% yield), MS: m/z=293 [M+H]⁺. ¹H-NMR (DMSO-d₆) δ 7.90 (s,1H), 7.83 (d, 2H), 7.58 (d, 1H), 7.48 (t, 1H), 7.38 (t, 1H), 6.52 (bs,2H), 4.62 (d, 2H), 3.85 (s, 3H).

Trans-3-(6-Amino-5-chloro-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methyl ester (A129)

Trans-3-(6-amino-5-chloro-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methyl ester was prepared fromtrans-methyl-3-aminocyclohexanecarboxylate hydrochloride using Method AA(53% yield). MS: m/z=285 [M+H]⁺. ¹H-NMR (DMSO-d₆) δ 7.86 (s, 1H), 6.46(bs, 2H), 5.98 (d, 1H), 4.07-3.98 (s, 3H), 2.00-1.43 (bm, 9H).

(1R,3S)-3-(6-Amino-5-chloro-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methyl ester (A130)

(1R,3S)-3-(6-amino-5-chloro-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methyl ester was prepared from(1R,3S)-3-amino-cyclohexanecarboxylic acid methyl ester hydrochlorideusing Method AA (42% yield). MS: m/z=285 [M+H]⁺. ¹H-NMR (DMSO-d₆) δ 7.86(s, 1H), 6.45 (bs, 2H), 6.24 (d, 1H), 4.05-3.92 (bm, 1H), 3.59 (s, 3H),2.47-2.41 (bm, 1H), 2.01-2.00 (bm, 1H), 1.83-1.77 (bm, 3H), 1.45-1.17(bm, 4H).

3-((6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-benzoicacid methyl ester (A131)

3-((6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-benzoicacid methyl ester was prepared from3-((6-amino-5-chloro-pyrimidin-4-ylamino)-methyl)-benzoic acid methylester using Method BB (63% yield). MS: m/z=427 [M+H]⁺. ¹H-NMR (DMSO-d₆)□δ 7.92 (s, 1H), 7.85 (s, 1H), 7.79 (d, 1H), 7.53 (d, 1H), 7.45-7.40 (m,3H), 7.29 (d, 2H), 7.19-7.11 (m, 5H), 6.17 (t, 1H), 5.52 (bs, 2H), 4.54(d, 2H), 3.84 (s, 3H).

Trans-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methyl ester (A132)

Trans-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methyl ester was prepared fromtrans-3-(6-amino-5-chloro-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methyl ester using Method BB (63% yield). MS: m/z=419 [M+H]⁺.¹H-NMR (DMSO-d₆) □δ 7.97 (s, 1H), 7.45 (dd, 2H), 7.28 (d, 2H), 7.26 (m,5H), 5.54 (bs, 1H), 4.60 (d, 1H), 4.11 (bd, 1H), 3.60 (s, 3H), 1.77-1.39(bm, 9H).

(1R,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methyl ester (A133)

(1R,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methyl ester was prepared from(1R,3S)-3-(6-amino-5-chloro-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methyl ester using Method BB (85% yield), MS: m/z=419 [M+H]⁺.

3-((6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-benzoicacid (134)

3-((6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-benzoicacid was prepared from3-((6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-benzoicacid methyl ester using Method CC (104% yield). MS: m/z=413 [M+H]⁺.¹H-NMR (DMSO-d₆) □δ 12.35 (bs, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.77 (d,1H), 7.49 (d, 1H), 7.44 (dd, 3H), 7.29 (d, 2H), 7.18 (m, 5H), 6.15 (t,3H), 5.51 (bs, 2H), 4.53 (d, 2H).

(1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid (A135)

(1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid was prepared from(1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methyl ester using Method CC (83% yield). MS: m/z=405 [M+H]⁺.¹H-NMR (DMSO-d₆) □δ 12.06 (bs, 1H), 7.97 (s, 1H), 7.44 (t, 2H), 7.28 (d,2H), 7.19 (m, 5H), 5.54 (bs, 2H), 4.57 (d, 1H), 4.12 (bs, 1H), 2.40 (bs,1H), 1.77-1.30 (bm, 8H).

(1R,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid (A136)

(1R,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid was prepared from(1R,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methyl ester using Method CC (71% yield). MS: m/z=405 [M+H]⁺.¹H-NMR (DMSO-d₆) 0b 11.99 (bs, 1H), 8.24 (s, 1H), 7.47 (t, 2H),7.26-7.13 (bm, 6H), 6.48 (bs, 2H), 6.10 (bs, 1H), 4.07-4.01 (bm, 1H),2.32-2.26 (bm, 1H), 1.84-1.71 (bm, 3H), 1.40-1.10 (bm, 5H).

(4-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-N-methoxy-N-methyl-acetamide(A137)

(4-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-N-methoxy-N-methyl-acetamidewas prepared from(4-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-acetic acidusing Method DD (51% yield). MS: m/z=456 [M+H]⁺. ¹H-NMR (DMSO-d₆) □δ8.05 (s, 1H), 7.45 (t, 4H), 7.34 (d, 2H), 7.19 (s, 1H), 7.16 (d, 5H),7.09 (d, 2H), 5.76 (bs, 2H), 3.66 (s, 3H), 3.64 (s, 2H), 3.10 (s, 3H).

3-((6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-N-methoxy-N-methyl-benzamide(A138)

3-((6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-N-methoxy-N-methyl-benzamidewas prepared from3-((6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-benzoicacid using Method DD (50% yield). MS: m/z=456 [M+H]⁺. ¹H-NMR (DMSO-d₆)□δ 7.96 (s, 1H), 7.44 (m, 4H), 7.36 (d, 2H), 7.26 (d, 2H), 7.14 (m, 5H),6.11 (t, 1H), 5.50 (bs, 1H), 4.52 (d, 2H), 3.50 (s, 3H), 3.23 (s, 3H).

(1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methoxy-methyl-amide (A139)

(1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methoxy-methyl-amide was prepared from(1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid using Method DD (43% yield). MS: m/z=448 [M+H]⁺. ¹H-NMR (DMSO-d₆)□δ 7.98 (s, 1H), 7.45 (t, 2H), 7.31 (d, 2H), 7.20 (t, 3H), 7.11 (d, 2H),5.76 (s, 1H), 5.61 (bs, 2H), 3.50 (s, 3H), 3.04 (s, 3H), 1.74-1.19 (bm,10H).

(1R,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methoxy-methyl-amide (A140)

(1R,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methoxy-methyl-amide was prepared from(1R,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid using Method DD (84% yield). MS: m/z=448 [M+H]⁺. ¹H-NMR (DMSO-d₆)□δ 7.96 (s, 4H), 7.45 (t, 2H), 7.22-7.09 (m, 5H), 5.46 (bs, 2H), 3.99(bs, 2H), 3.68 (s, 3H), 3.31 (s, 3H), 1.80-1.64 (bm, 3H), 1.61 (bd, 1H),1.38-1.09 (bm, 4H).

1-(3-((6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-but-2-yn-1-one(A141)

1-(3-((6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-but-2-yn-1-onewas prepared from using3-((6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-N-methoxy-N-methyl-benzamideMethod FF (13% yield). MS: m/z=435 [M+H]⁺. ¹H-NMR (DMSO-d₆) □δ 8.34 (s,1H), 7.97 (t, 2H), 7.60 (d, 2H), 7.55 (t, 1H), 7.47 (t, 2H), 7.34 (d,2H), 7.22 (t, 3H), 7.14 (d, 2H), 7.00 (bs, 2H), 4.46 (d, 2H), 2.20 (s,3H). ccc

1-(3-((6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-but-2-en-1-one(A142)

1-(3-((6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-but-2-en-1-onewas prepared from3-((6-amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-N-methoxy-N-methyl-benzamideusing Method EE (20% yield). MS: m/z=437 [M+H]⁺. ¹H-NMR (DMSO-d₆) □δ8.33 (s, 1H), 7.86 (bt, 2H), 7.56-7.43 (m, 5H), 7.34 (d, 2H), 7.22-7.08(m, 6H), 7.01 (m, 3H), 4.65 (d, 2H), 1.98 (d, 3H).

1-((1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-propenone(A143)

1-((1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-propenonewas prepared from(1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methoxy-methyl-amide using Method GG (24% yield). MS: m/z=415[M+H]⁺. ¹H-NMR (DMSO-d₆) □δ 8.35 (s, 1H), 7.47 (t, 2H), 7.32 (d, 2H),7.21-7.13 (m, 5H), 6.91 (bs, 2H), 6.56 (dd, 1H), 6.21 (d, 1H), 5.83 (d,1H), 4.28 (bs, 1H), 3.00 (t, 1H), 1.85-1.38 (bm, 9H).

1-((1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-en-1-one(A144)

1-((1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-en-1-onewas prepared from(1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methoxy-methyl-amide using Method EE (35% yield). MS: m/z=429[M+H]⁺. ¹H-NMR (DMSO-d₆) δ 8.35 (s, 1H), 7.47 (t, 2H), 7.32 (d, 2H),7.23-7.13 (m, 5H), 6.94 (bs, 2H), 6.84 (m, 1H), 6.28/6.32 (s, 1H), 6.24(bs, 1H), 4.29 (bs, 1H), 2.90 (t, 1H), 1.87 (d, 3H), 1.49-1.35 (m, 8H).

1-((1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-yn-1-one(A145)

1-((1S,3S)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-yn-1-onewas prepared from(1S,3S)-3-(6-A=amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methoxy-methyl-amide using Method FF (44% yield). MS: m/z=427[M+H]⁺. ¹H-NMR (DMSO-d₆) □δ 8.35 (s, 1H), 7.48 (t, 2H), 7.30 (d, 2H),7.23-7.13 (bm, 5H), 6.91 (bs, 2H), 6.36 (bs, 1H), 4.16 (bs, 1H), 2.75(t, 1H), 2.08-1.25 (bm, 12H).

1-((1S,3R)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-en-1-one(A146)

1-((1S,3R)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-en-1-onewas prepared from(1S,3R)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methoxy-methyl-amide using Method EE (23% yield). MS: m/z=429[M+H]⁺. ¹H-NMR (DMSO-d₆) □δ 8.35 (s, 1H), 7.47 (t, 2H), 7.47-7.13 (m,6H), 6.90-6.85 (bm, 3H), 6.68 (bd, 1H), 6.22 (ss, 1H), 4.11 (bs, 1H),2.79 (bm, 1H), 1.88 (d, 3H), 1.74 (bs, 4H), 1.46-1.00 (bm, 5H).

1-((1S,3R)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-yn-1-one(A147)

1-((1S,3R)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-yn-1-onewas prepared from(1S,3R)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylicacid methoxy-methyl-amide using Method FF (31% yield). MS: m/z=427[M+H]⁺. ¹H-NMR (DMSO-d₆) δ 8.35 (s, 1H), 7.47 (t, 2H), 7.27 (d, 2H),7.22 (t, 3H), 7.17 (m, 4H), 6.92 (bs, 2H), 6.67 (d, 1H), 4.09 (bs, 2H),2.07 (s, 3H), 1.95 (bm, 2H), 1.79-1.70 (bm, 2H), 1.44-1.25 (bm, 3H),1.08-1.14 (bm, 1H).

(S)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one(A148)

(S)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, (S)-tert-butyl3-aminopyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, andacryloyl chloride using methods B, C, D and F. HPLC: 100%. MS: m/z=402[M+H]⁺.

N-(3-((2-amino-3-(4-(benzyloxy)phenyl)pyridin-4-yl)oxy)phenyl)acrylamide(A149)

N-(3-((2-amino-3-(4-(benzyloxy)phenyl)pyridin-4-yl)oxy)phenyl)acrylamidewas prepared from 4-chloro-3-iodopyridin-2-amine, 3-aminophenol,(4-(benzyloxy)phenyl)boronic acid, and acryloyl chloride using methodsA, C, and F. HPLC: 100%. MS: m/z=438 [M+H]⁺. ¹H-NMR (DMSO-D6) δ 10.36(s, 1H), 7.92 (d, 1H), 7.64 (s, 1H), 7.47-7.32 (m, 11H), 7.16 (d, 2H),6.86 (m, 1H), 6.40 (dd, 1H), 6.33 (d, 1H), 6.24 (d, 1H), 5.77 (d, 1H),5.13 (s, 2H).

1-(3-((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one(A150)

1-(3-((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-onewas prepared from 5-bromo-4-chloropyrimidin-2-amine, tert-butyl3-aminopiperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, andacryloyl chloride using methods B, C, D and F. HPLC: 97%. MS: m/z=416[M+H]⁺.

(E)-N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide(A151)

(E)-N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamidewas prepared from 4-chloro-3-iodopyridin-2-amine, 3-aminophenol,(4-phenoxyphenyl)boronic acid, and (E)-4-(dimethylamino)but-2-enoic acidhydrochloride using methods A, C, and E. HPLC: 100%. MS: m/z=481 [M+H]⁺.¹H-NMR (DMSO-D6) δ 10.51 (s, 1H), 9.88 (broad s, 1H), 7.95 (d, 1H), 7.61(s, 1H), 7.43-7.32 (m, 8H), 7.17 (t, 1H), 7.12-7.08 (m, 4H), 6.89 (s,1H), 6.72 (m, 1H), 6.42 (d, 1H), 6.32 (d, 1H), 3.93 (d, 2H), 2.79 (s,6H).

(E)-N-(3-((2-amino-3-(4-(benzyloxy)phenyl)pyridin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide(A152)

(E)-N-(3-((2-amino-3-(4-(benzyloxy)phenyl)pyridin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamidewas prepared from 4-chloro-3-iodopyridin-2-amine, 3-aminophenol,(4-(benzyloxy)phenyl)boronic acid, and (E)-4-(dimethylamino)but-2-enoicacid hydrochloride using methods A, C, and E. HPLC: 100%. MS: m/z=495[M+H]⁺. ¹H-NMR (DMSO-D6) δ 10.51 (s, 1H), 9.90 (broad s, 1H), 7.92 (d,1H), 7.59 (s, 1H), 7.47-7.27 (m, 11H), 7.16 (d, 2H), 6.88 (s, 1H), 6.72(m, 1H), 6.42 (d, 1H), 6.30 (d, 1H), 5.13 (s, 2H), 3.93 (d, 2H), 2.79(s, 6H).

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one(A153)

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid,and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride using methods B,C, D, and E. HPLC: 100%. MS: m/z=487 [M+H]⁺.

N-cis-4-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide(A154)

N-cis-4-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine,tert-butyl-(cis-4-aminocyclohexyl)carbamate,(4-(benzyloxy)phenyl)boronic acid, and acryloyl chloride using method B,C, D, and F. HPLC: 99%. MS: m/z=444 [M+H]⁺. ¹H-NMR (DMSO-D6) δ 8.33 (s,1H), 7.78 (d, 1H), 7.51 (d, 2H), 7.43 (t, 2H), 7.37 (t, 1H), 7.25 (s,4H), 6.81 (broad s, 2H), 6.27 (dd, 1H), 6.06 (d, 1H), 5.79 (broad s,1H), 5.55 (d, 1H), 5.16 (s, 2H), 4.00 (s, 1H), 3.81 (s, 1H), 1.56 (s,8H).

4-(4-(((1-acryloylpyrrolidin-3-yl)methyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamide(A155)

4-(4-(((1-acryloylpyrrolidin-3-yl)methyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl3-(aminomethyl)pyrrolidine-1-carboxylate,N-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, andacryloyl chloride using methods B, C, D, and F. HPLC: 100%. MS: m/z=443[M+H]⁺.

1-(3-(((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one(A156)

1-(3-(((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl3-(aminomethyl)pyrrolidine-1-carboxylate, (4-(benzyloxy)phenyl)boronicacid, and acryloyl chloride using methods B, C, D, and F. HPLC: 97%. MS:m/z=430 [M+H]⁺.

4-(4-(((1-acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamide(A157)

4-(4-(((1-acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,N-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide andacryloylchloride using methods B, C, D and F. HPLC: 99%. MS: m/z=457[M+H]⁺.

N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)-4-fluorophenyl)acrylamide(A158)

N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)-4-fluorophenyl)acrylamidewas prepared from 4-chloro-3-iodopyridin-2-amine,5-amino-2-fluorophenol, (4-phenoxyphenyl)boronic acid and acryloylchloride using methods A, C, and F. HPLC: 100%. MS: m/z=442 [M+H]⁺.¹H-NMR (DMSO-D6) δ 10.35 (s, 1H), 7.96 (d, 1H), 7.79 (d, 1H), 7.45-7.38(m, 6H), 7.21-7.10 (m, 6H), 6.41-6.36 (m, 2H), 6.26 (d, 1H), 5.79 (d,1H).

4-(4-((cis-4-acrylamidocyclohexyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamide(A159)

4-(4-((cis-4-acrylamidocyclohexyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamidewas prepared from 5,6-dichloropyrimidin-4-amine,tert-butyl-(cis-4-aminocyclohexyl)carbamate,N-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, andacryloyl chloride using methods B, C, D, and E. HPLC: 100%. MS: m/z=457[M+H]⁺.

(E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one(A160)

(E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl3-aminopiperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and(E)-4-(dimethylamino)but-2-enoic acid hydrochloride using methods B, C,D, and E. HPLC: 100%. MS: m/z=473 [M+H]⁺.

N-(3-((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamide(A161)

N-(3-((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 5-amino-2-fluorophenol,2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, andacryloyl chloride using methods A, C, and F. HPLC: 100%. MS: m/z=444[M+H]⁺. ¹H-NMR (DMSO-D6) δ 10.16 (s, 1H), 8.09 (s, 1H), 7.99 (s, 1H),7.80 (d, 1H), 7.59 (d, 1H), 7.38-7.32 (m, 3H), 7.21-6.91 (m, 5H), 6.70(broad s, 2H), 6.31 (dd, 1H), 6.18 (d, 1H), 5.69 (d, 1H).

N-(3-((6-amino-5-(4-(pyridin-2-yloxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A162)

N-(3-((6-amino-5-(4-(pyridin-2-yloxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine, andacryloyl chloride using methods A, C, and F. HPLC: 100%. MS: m/z=426[M+H]⁺. ¹H-NMR (DMSO-D6) δ 10.22 (s, 1H), 8.20 (d, 1H), 8.08 (s, 1H),7.87 (t, 1H), 7.50 (s, 1H), 7.46 (d, 2H), 7.39 (d, 1H), 7.30 (t, 1H),7.23 (d, 2H), 7.16 (m, 1H), 7.07 (d, 1H), 6.80 (d, 1H), 6.58 (broad s,2H), 6.41 (dd, 1H), 6.25 (d, 1H), 5.76 (d, 1H).

N-(3-((6-amino-5-(3-sulfamoylphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A163)

N-(3-((6-amino-5-(3-sulfamoylphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide, andacryloyl chloride using methods A, C, and F. HPLC: 98%. MS: m/z=412[M+H]⁺. ¹H-NMR (DMSO-D6) δ 10.17 (s, 1H), 8.04 (s, 1H), 7.79-7.75 (m,2H), 7.61-7.58 (m, 2H), 7.43 (s, 1H), 7.32-7.30 (m, 3H), 7.23 (t, 1H),6.77-6.52 (m, 3H), 6.34 (dd, 1H), 6.18 (d, 1H), 5.70 (d, 1H).

N-(3-((6-amino-5-(3-(trifluoromethoxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A164)

N-(3-((6-amino-5-(3-(trifluoromethoxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,(3-(trifluoromethoxy)phenyl)boronic acid, and acryloyl chloride usingmethods A, C, and F. HPLC: 100%. MS: m/z=417 [M+H]⁺. ¹H-NMR (DMSO-D6) δ10.22 (s, 1H), 8.09 (s, 1H), 7.59 (t, 1H), 7.48-7.44 (m, 2H), 7.39-7.36(m, 3H), 7.28 (t, 1H), 6.95-6.55 (m, 3H), 6.39 (dd, 1H), 6.23 (d, 1H),5.75 (d, 1H).

N-(3-((6-amino-5-(6-(2-fluorophenoxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A165)

N-(3-((6-amino-5-(6-(2-fluorophenoxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,2-(2-fluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine,and acryloyl chloride using methods A, C, and F. HPLC: 99%. MS: m/z=444[M+H]⁺. ¹H-NMR (DMSO-D6) δ 10.16 (s, 1H), 8.07 (s, 1H), 8.02 (s, 1H),7.84 (d, 1H), 7.42 (s, 1H), 7.32-7.15 (m, 7H), 6.86-6.60 (m, 3H), 6.34(dd, 1H), 6.18 (d, 1H), 5.69 (d, 1H).

N-(3-((6-amino-5-(6-(4-fluorophenoxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A166)

N-(3-((6-amino-5-(6-(4-fluorophenoxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,2-(4-fluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine,and acryloyl chloride using methods A, C, and F. HPLC: 99%. MS: m/z=444[M+H]⁺. ¹H-NMR (DMSO-D6) δ 10.17 (s, 1H), 8.09 (d, 1H), 8.03 (s, 1H),7.82 (d, 1H), 7.43 (s, 1H), 7.30 (d, 1H), 7.25-7.15 (m, 6H), 7.07 (d,1H), 6.92-6.58 (m, 3H), 6.34 (dd, 1H), 6.18 (d, 1H), 5.70 (d, 1H).

N-(6-((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyridin-2-yl)acrylamideMSC2375022 (A167)

N-(6-((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyridin-2-yl)acrylamidewas prepared from 5-bromo-4-chloropyrimidine, pyridine-2,6-diamine,(4-phenoxyphenyl)boronic acid, and acryloyl chloride using methods H, C,and F. HPLC: 97%. MS: m/z=410 [M+H]⁺. ¹H-NMR (DMSO-D6) δ 10.43 (s, 1H),8.75 (s, 1H), 8.33 (s, 1H), 8.04 (broad s, 1H), 7.85-7.73 (m, 3H), 7.48(d, 2H), 7.39 (t, 2H), 7.15 (t, 1H), 7.07 (d, 2H), 7.03 (d, 2H), 6.47(dd, 1H), 6.22 (d, 1H), 5.70 (d, 1H).

1-(4-(((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A168)

1-(4-(((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, andacryloyl chloride using methods B, C, D, and F. HPLC: 100%. MS: m/z=431[M+H]⁺.

1-(4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)prop-2-en-1-one(A169)

1-(4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate,(4-(3-(trifluoromethyl)phenoxy)phenyl)boronic acid, and acryloylchloride using methods B, C, D, and F. HPLC: 99%. MS: m/z=514 [M+H]⁺. ¹HNMR (500 MHz, dmso) δ 7.88 (s, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.44 (d,J=7.8 Hz, 1H), 7.38 (s, 1H), 7.32 (dd, J=8.2, 2.3 Hz, 1H), 7.22 (dd,J=6.5, 4.6 Hz, 2H), 7.14 (t, 2H), 6.71 (dd, 10.5 Hz, 1H), 5.99 (dd, 1H),5.63-5.52 (m, 3H), 5.15 (t, 1H), 5.09 (s, 1H), 3.94 (d, 1H), 3.66 (d,1H), 2.96 (t, 1H), 1.40-1.20 (m, 5H), 0.79 (t, 1H).

1-((3S,4S)-4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-en-1-one(A170)

1-((3S,4S)-4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, (3S,4S)-tert-butyl4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate,(4-(3-trifluoromethyl)phenoxy)phenyl)boronic acid, and acryloyl chlorideusing methods B, C, D, and F. HPLC: 100%. MS: m/z=514 [M+H]⁺. ¹H NMR(400 MHz, DMSO) b 7.95 (d, J=5.4 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.51(d, J=7.8 Hz, 1H), 7.45 (s, 1H), 7.38 (dd, 1H), 7.31-7.24 (m, 2H), 7.19(d, 2H), 6.79-6.69 (m, 1H), 6.06 (d, 1H), 5.69-5.57 (m, 2H), 5.54 (s,2H), 5.39 (bs, 1H), 4.41 (d, 1H), 4.22 (d, 1H), 3.93 (t, 1H), 3.49-3.35(m, 2H), 3.16-2.99 (m, 1H), 2.86 (dt, 1H), 2.61 (t, 1H), 2.34 (t, 1H),1.60 (bs, 2H), 1.13-0.96 (m, 1H).

1-(4-(((6-amino-2′-phenoxy-[5,5′-bipyrimidin]-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A171)

1-(4-(((6-amino-2′-phenoxy-[5,5′-bipyrimidin]-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine, andacryloyl chloride using methods B, C, D, and F. MS: m/z=432 [M+H]⁺. ¹HNMR (400 MHz, DMSO) b 8.37 (s, 2H), 7.96 (s, 1H), 7.47 (t, 2H),7.30-7.20 (m, 3H), 6.76 (dd, 1H), 6.10-5.97 (m, 2H), 5.80 (s, 2H), 5.62(dd, 1H), 4.35 (d, 1H), 3.99 (d, 1H), 3.10 (t, 2H), 3.02-2.89 (m, 1H),2.56 (m, 1H), 1.81 (m, 1H), 1.63 (d, 2H), 1.02-0.83 (m, 2H).

N-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A172)

N-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and acryloyl chloride using methods A, C, and F. HPLC: 100%. MS: m/z=413[M+H]⁺. ¹H-NMR (DMSO-D6) δ 10.18 (s, 1H), 8.08 (s, 1H), 7.98 (s, 1H),7.66 (s, 1H), 7.45 (s, 1H), 7.33 (t, 1H), 7.29-7.20 (m, 6H), 6.99-6.64(m, 3H), 6.34 (dd, 1H), 6.18 (d, 1H), 5.70 (d, 1H), 5.30 (s, 2H).

N-((1S,3R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide(A173)

N-((1S,3R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl(cis-3-aminocyclohexyl)carbamate, (4-phenoxyphenyl)boronic acid, andacryloyl chloride using methods B, C, D, F and chiral separation. HPLC:95%. MS: m/z=430 [M+H]⁺.

N-((1R,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide(A174)

N-((1R,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl(cis-3-aminocyclohexyl)carbamate, (4-phenoxyphenyl)boronic acid, andacryloyl chloride using methods B, C, D, F and chiral separation. HPLC:98%. MS: m/z=430 [M+H]⁺.

N-((1R,3R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide(A175)

N-((1R,3R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl(trans-3-aminocyclohexyl)carbamate, (4-phenoxyphenyl)boronic acid, andacryloyl chloride using methods B, C, D, F and chiral separation. HPLC:98%. MS: m/z=430 [M+H]⁺.

N-((1S,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide(A176)

N-((1S,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl(trans-3-aminocyclohexyl)carbamate, (4-phenoxyphenyl)boronic acid, andacryloyl chloride using methods B, C, D, F and chiral separation. HPLC:97%. MS: m/z=430 [M+H]⁺.

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.1.1]hexan-1-yl)acrylamide(A177)

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.1.1]hexan-1-yl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, benzyl(4-aminobicyclo[2.1.1]hexan-1-yl)carbamate hydrochloride,(4-phenoxyphenyl)boronic acid, and acryloyl chloride using methods B, C,hydrogenation, and F. HPLC: 100%. MS: m/z=428 [M+H]⁺. ¹H-NMR (DMSO-d₆) δ8.46 (s, 1H), 8.32 (s, 1H), 7.44 (t, 2H), 7.27-7.12 (m, 8H), 6.85 (broads, 2H), 6.18 (dd, 1H), 6.04 (d, 1H), 5.54 (d, 1H), 1.99-1.94 (m, 4H),1.85-1.81 (m, 4H).

(R)—N4-(1-((perfluorophenyl)sulfonyl)pyrrolidin-3-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine(A178)

(R)—N4-(1-((perfluorophenyl)sulfonyl)pyrrolidin-3-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diaminewas prepared from 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl3-aminopyrrolidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and2,3,4,5,6-pentafluorobenzene-1-sulfonyl chloride using methods B, C, D,and addition using pyridine in final step. HPLC: 99%. MS: m/z=578[M+H]⁺.

(R)—N4-(1-((perfluorophenyl)sulfonyl)piperidin-3-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine(A179)

(R)—N4-(1-((perfluorophenyl)sulfonyl)piperidin-3-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diaminewas prepared from 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl3-aminopiperidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, and2,3,4,5,6-pentafluorobenzene-1-sulfonyl chloride using methods B, C, D,and addition using pyridine in final step. HPLC: 96%. MS: m/z=592[M+H]⁺.

(R)-1-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one(A180)

(R)-1-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl3-aminopiperidine-1-carboxylate,1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and acryloyl chloride using methods B, C, D, and F. HPLC: 100%. MS:m/z=404 [M+H]⁺.

N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclopentyl)acrylamide(A181)

N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclopentyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl(cis-3-aminocyclopentyl)carbamate, (4-phenoxyphenyl)boronic acid, andacryloyl chloride using methods B, C, D, and F. HPLC: 98%. MS: m/z=416[M+H]⁺. ¹H-NMR (DMSO-d6) δ 8.36 (s, 1H), 8.11 (d, 1H), 7.45 (t, 2H),7.28-7.12 (m, 7H), 7.07-6.82 (m, 3H), 6.15 (dd, 1H), 6.04 (d, 1H), 5.56(d, 1H), 4.43 (broad s, 1H), 3.96 (sextet, 1H), 2.22 (m, 1H), 1.90-1.80(m, 2H), 1.68-1.43 (m, 3H).

N-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)cyclobutyl)acrylamide(A182)

N-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)cyclobutyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl(3-(aminomethyl)cyclobutyl)carbamate, (4-phenoxyphenyl)boronic acid, andacryloyl chloride using methods B, C, D, and F. HPLC: 100%. MS: m/z=416[M+H]⁺.

N-(3-((6-amino-5-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A183)

N-(3-((6-amino-5-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,1-(3,5-difluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and acryloyl chloride using methods A, C, and F. HPLC: 100%. MS: m/z=449[M+H]⁺. ¹H-NMR (DMSO-d₆) δ 10.23 (s, 1H), 8.19 (s, 1H), 8.09 (s, 1H),7.77 (s, 1H), 7.54 (s, 1H), 7.41 (d, 1H), 7.32 (t, 1H), 7.16 (t, 1H),7.14-6.78 (m, 5H), 6.42 (dd, 1H), 6.25 (d, 1H), 5.76 (d, 1H), 5.42 (s,2H).

N-(3-((6-amino-5-(1-(2-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A184)

N-(3-((6-amino-5-(1-(2-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,1-(2-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and acryloyl chloride using methods A, C, and F. HPLC: 100%. MS: m/z=431[M+H]⁺. ¹H-NMR (DMSO-d₆) δ 10.21 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H),7.73 (s, 1H), 7.50 (s, 1H), 7.40-7.17 (m, 6H), 6.82-6.65 (m, 3H), 6.42(dd, 1H), 6.25 (d, 1H), 5.77 (d, 1H), 5.43 (s, 2H).

1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)azetidin-1-yl)prop-2-en-1-one(A185)

1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)azetidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl3-aminoazetidine-1-carboxylate, (4-phenoxyphenyl)boronic acid, andacryloyl chloride using methods B, C, D, and F. HPLC: 100%. MS: m/z=388[M+H]⁺. ¹H-NMR (DMSO-d₆) δ 8.33 (s, 1H), 7.45 (t, 2H), 7.30-7.13 (m,8H), 6.83 (broad s, 1.5H), 6.28 (dd, 1H), 6.08 (d, 1H), 5.66 (d, 1H),4.90 (m, 1H), 4.44 (t, 1H), 1.12 (q, 2H), 3.87 (m, 1H).

N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)acrylamide(A186)

N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, pyridine-3,5-diamine,(4-phenoxyphenyl)boronic acid, and acryloyl chloride using methods J, C,and F. HPLC: 100%. MS: m/z=425 [M+H]⁺.

N-(3-((6-amino-5-(1-(4-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A187)

N-(3-((6-amino-5-(1-(4-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,1-(4-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and acryloyl chloride using methods A, C, and F. HPLC: 99%. MS: m/z=431[M+H]⁺. ¹H-NMR (DMSO-d₆) δ 10.22 (s, 1H), 8.14 (s, 1H), 8.04 (s, 1H),7.73 (s, 1H), 7.52 (s, 1H), 7.39-7.32 (m, 4H), 7.17 (t, 2H), 6.95-6.68(m, 2.5H), 6.42 (dd, 1H), 6.25 (d, 1H), 5.77 (d, 1H), 5.36 (s, 2H).

N-((1R,3S,5R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-hydroxycyclohexyl)acrylamide(racemic) (A188)

N-((1R,3S,5R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-hydroxycyclohexyl)acrylamide(racemic) was prepared from 5,6-dichloropyrimidin-4-amine,(1R,3S,5r)-5-((tert-butyldimethylsilyl)oxy)cyclohexane-1,3-diaminedihydrochloride (racemic), (4-phenoxyphenyl)boronic acid, and acryloylchloride using methods B, C, deprotection with TBAF, and F. HPLC: 97%.MS: m/z=446 [M+H]⁺.

N-(5-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-3-yl)acrylamide(A189)

N-(5-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-3-yl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 5-aminopyridin-3-oldihydrochloride,1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and acryloyl chloride using methods A, C, and F. HPLC: 77%. MS: m/z=414[M+H]⁺.

N-(3-((6-amino-5-(1-(3-methylbenzyl)-H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A190)

N-(3-((6-amino-5-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,1-(3-methylbenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and acryloyl chloride using methods A, C, and F. HPLC: 100%. MS: m/z=427[M+H]⁺. ¹H-NMR (DMSO-d₆) δ 10.21 (s, 1H), 8.12 (s, 1H), 8.02 (s, 1H),7.72 (s, 1H), 7.51 (s, 1H), 7.40 (d, 1H), 7.31 (t, 1H), 7.22 (t, 1H),7.11 (m, 3H), 6.82-6.63 (m, 2.7H), 6.42 (dd, 1H), 6.25 (d, 1H), 5.76 (d,1H), 5.32 (s, 2H), 2.27 (s, 3H).

N-(3-((6-amino-5-(1-(3-chlorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A191)

N-(3-((6-amino-5-(1-(3-chlorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,1-(3-chlorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and acryloyl chloride using methods A, C, and F. HPLC: 99%. MS: m/z=447[M+H]⁺. ¹H-NMR (DMSO-d₆) δ 10.21 (s, 1H), 8.18 (s, 1H), 8.03 (s, 1H),7.75 (s, 1H), 7.52 (s, 1H), 7.42-7.26 (m, 6H), 6.96-6.65 (m, 2.6H), 6.42(dd, 1H), 6.25 (d, 1H), 5.76 (d, 1H), 5.39 (s, 2H).

(R)-1-(2-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-one(A192)

(R)-1-(2-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl2-(hydroxymethyl)morpholine-4-carboxylate,1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and acryloyl chloride using methods A, C, D, and F. HPLC: 99%. MS:m/z=421 [M+H]⁺.

(S)-1-(2-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-one(A193)

(S)-1-(2-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, (S)-tert-butyl2-(hydroxymethyl)morpholine-4-carboxylate,1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and acryloyl chloride using methods A, C, D, and F. HPLC: 100%. MS:m/z=421 [M+H]⁺.

N-(3-((6-amino-5-(1-(2-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A194)

N-(3-((6-amino-5-(1-(2-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)benzonitrile,and acryloyl chloride using methods A, C, and F. HPLC: 96%. MS: m/z=438[M+H]⁺. ¹H-NMR (DMSO-d₆) δ 10.21 (s, 1H), 8.21 (s, 1H), 8.01 (s, 1H),7.88 (d, 1H), 7.75 (s, 1H), 7.69 (t, 1H), 7.54-7.29 (m, 5H), 6.81 (d,1H), 6.66 (broad s, 2H), 6.42 (dd, 1H), 6.25 (d, 1H), 5.77 (d, 1H), 5.59(s, 2H).

N-(3-((6-amino-5-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A195)

N-(3-((6-amino-5-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(3-(trifluoromethyl)benzyl)-1H-pyrazole,and acryloyl chloride using methods A, C, and F. HPLC: 98%. MS: m/z=481[M+H]⁺. ¹H-NMR (DMSO-d₆) δ 10.20 (s, 1H), 8.20 (s, 1H), 8.00 (s, 1H),7.75-7.29 (m, 8H), 6.93-6.58 (m, 3H), 6.42 (dd, 1H), 6.25 (d, 1H), 5.77(d, 1H), 5.49 (s, 2H).

(R)-1-(3-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one(A196)

(R)-1-(3-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-onewas prepared from 5-bromo-6-chloropyrimidin-4-amine, (R)-tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate,1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and acryloyl chloride using methods A, C, D, and F. HPLC: 99%. MS:m/z=405 [M+H]⁺.

N-(5-((6-amino-5-(4-(4-cyanophenoxy)phenyl)pyrimidin-4-yl)oxy)pyridin-3-yl)acrylamide(A197)

N-(5-((6-amino-5-(4-(4-cyanophenoxy)phenyl)pyrimidin-4-yl)oxy)pyridin-3-yl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 5-aminopyridin-3-oldihydrochloride,4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile,and acryloyl chloride using methods A, C, and F. HPLC: 98%. MS: m/z=452[M+H]⁺. ¹H-NMR (DMSO-d₆) δ 10.48 (s, 1H), 8.57 (s, 1H), 8.12-8.09 (m,2H), 7.97 (t, 1H), 7.86 (d, 2H), 7.52 (d, 2H), 7.23 (t, 4H), 6.43 (dd,1H), 6.29 (d, 1H), 5.83 (d, 1H).

N-(3-((6-amino-5-(1-(3-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A198)

N-(3-((6-amino-5-(1-(3-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,1-(3-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and acryloyl chloride using methods A, C, and F. HPLC: 99%. MS: m/z=443[M+H]⁺. ¹H-NMR (DMSO-d₆) δ 10.20 (s, 1H), 8.13 (s, 1H), 7.99 (s, 1H),7.72 (s, 1H), 7.49 (s, 1H), 7.41 (d, 1H), 7.33-7.23 (m, 2H), 6.87-6.79(m, 4H), 6.63 (broad s, 2H), 6.42 (dd, 1H), 6.25 (d, 1H), 5.76 (d, 1H),5.33 (s, 2H), 3.70 (s, 3H).

4-(4-(4-((((3S,4S)-1-acryloyl-3-hydroxypiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile(A199)

4-(4-(4-((((3S,4S)-1-acryloyl-3-hydroxypiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile(racemic) was prepared from 5,6-dichloropyrimidin-4-amine,(3S,4S)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate(racemic),4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile,and acryloyl chloride using methods B, C, D, and F. HPLC: 100%. MS:m/z=471 [M+H]⁺.

(R)-4-(4-(4-((4-acryloylmorpholin-2-yl)methoxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile(A200)

(R)-4-(4-(4-((4-acryloylmorpholin-2-yl)methoxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitrilewas prepared from 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl2-(hydroxymethyl)morpholine-4-carboxylate,4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile,and acryloyl chloride using methods A, C, D, and F. HPLC: 99%. MS:m/z=458 [M+H]⁺.

(R)-4-(4-(4-((1-acryloylpyrrolidin-3-yl)methoxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile(A201)

(R)-4-(4-(4-((1-acryloylpyrrolidin-3-yl)methoxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitrilewas prepared from 5,6-dichloropyrimidin-4-amine, (R)-tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate,4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile,and acryloyl chloride using methods A, C, D, and F. HPLC: 99%. MS:m/z=442 [M+H]⁺.

4-(4-(4-((2-acryloyl-2-azaspiro[3.3]heptan-6-yl)oxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile(A202)

4-(4-(4-((2-acryloyl-2-azaspiro[3.3]heptan-6-yl)oxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitrilewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate,4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile,and acryloyl chloride using methods A, C, D, and F. HPLC: 100%. MS:m/z=454 [M+H]⁺.

N-(3-((6-amino-5-(1-(3-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A203)

N-(3-((6-amino-5-(1-(3-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)benzonitrile,and acryloyl chloride using methods A, C, and F. HPLC: 100%. MS: m/z=438[M+H]⁺. ¹H-NMR (DMSO-d₆) δ 10.20 (s, 1H), 8.18 (s, 1H), 8.00 (s, 1H),7.79-7.74 (m, 3H), 7.65-7.50 (m, 3H), 7.41 (d, 1H), 7.31 (t, 1H), 6.81(d, 1H), 6.69 (broad s, 2H), 6.42 (dd, 1H), 6.25 (d, 1H), 5.77 (d, 1H),5.44 (s, 2H).

1-((3S,5S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-fluoropiperidin-1-yl)prop-2-en-1-one(A204)

1-((3S,5S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-fluoropiperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine,(3S,5S)-5-fluoro-1-(4-methoxybenzyl)piperidin-3-amine,(4-phenoxyphenyl)boronic acid, and acryloyl chloride using methods B, C,hydrogenation, and F. HPLC: 97%. MS: m/z=434 [M+H]⁺.

1-((3R,5R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-fluoropiperidin-1-yl)prop-2-en-1-one(A205)

1-((3R,5R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-fluoropiperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine,(3R,5R)-5-fluoro-1-(4-methoxybenzyl)piperidin-3-amine,(4-phenoxyphenyl)boronic acid, and acryloyl chloride using methods B, C,hydrogenation, and F. HPLC: 99%. MS: m/z=434 [M+H]⁺.

methyl3-((4-(4-(3-acrylamidophenoxy)-6-aminopyrimidin-5-yl)-1H-pyrazol-1-yl)methyl)benzoate(A206)

methyl3-((4-(4-(3-acrylamidophenoxy)-6-aminopyrimidin-5-yl)-1H-pyrazol-1-yl)methyl)benzoatewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol, methyl3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)benzoate,and acryloyl chloride using methods A, C, and F. HPLC: 94%. MS: m/z=471[M+H]⁺. ¹H-NMR (DMSO-d₆) δ 10.20 (s, 1H), 8.18 (s, 1H), 7.99 (s, 1H),7.94 (s, 1H), 7.89 (d, 1H), 7.74 (s, 1H), 7.59 (d, 1H), 7.53-7.49 (m,2H), 7.41 (d, 1H), 7.31 (t, 1H), 6.81 (d, 1H), 6.65 (broad s, 2H), 6.42(dd, 1H), 6.25 (d, 1H), 5.77 (d, 1H), 5.46 (s, 2H), 3.83 (s, 3H).

4-(4-(4-((2-acryloyl-2-azaspiro[3.3]heptan-6-yl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile(A207)

4-(4-(4-((2-acryloyl-2-azaspiro[3.3]heptan-6-yl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrilewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl6-amino-2-azaspiro[3.3]heptane-2-carboxylate,4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile,and acryloyl chloride using methods B, C, D, and E. HPLC: 98%. MS:m/z=453 [M+H]⁺. ¹H-NMR (DMSO-d₆) δ 7.96 (s, 1H), 7.87 (d, 2H), 7.29-7.23(m, 6H), 6.31-6.22 (m, 1H), 6.07 (d, 1H), 5.67-5.46 (m, 4H), 4.40 (q,1H), 4.25 (s, 1H), 4.08 (s, 1H), 3.96 (s, 1H), 3.79 (s, 1H), 2.47-2.40(m, 2H), 2.14-2.09 (m, 2H).

4-(4-(4-(((8-acryloyl-8-azabicyclo[3.2.1]octan-3-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile(A208)

4-(4-(4-(((8-acryloyl-8-azabicyclo[3.2.1]octan-3-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrilewas prepared from 5-bromo-6-chloropyrimidin-4-amine, tert-butyl3-(aminomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate,4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile,and acryloyl chloride using methods B, C, D, and F. HPLC: 98%. MS:m/z=481 [M+H]⁺.

1-(3-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one(A209)

1-(3-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-onewas prepared from 5-bromo-6-chloropyrimidin-4-amine, tert-butyl3-(aminomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate,1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and acryloyl chloride using methods B, C, D, and F. HPLC: 99%. MS:m/z=444 [M+H]⁺.

1-((3R,4R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-4-hydroxypiperidin-1-yl)prop-2-en-1-one(racemic) (A210)

1-((3R,4R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-4-hydroxypiperidin-1-yl)prop-2-en-1-one(racemic) was prepared from 5,6-dichloropyrimidin-4-amine,(3R,4R)-benzyl 3-amino-4-hydroxypiperidine-1-carboxylate (racemic),(4-phenoxyphenyl)boronic acid, and acryloyl chloride using methods B, C,hydrogenation, and F. HPLC: 100%. MS: m/z=432 [M+H]⁺.

N-(3-((6-amino-5-(1-(3-(methylsulfonyl)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A211)

N-(3-((6-amino-5-(1-(3-(methylsulfonyl)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,1-(3-(methylsulfonyl)benzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,and acryloyl chloride using methods A, C, and F. HPLC: 83%. MS: m/z=456[M+H]⁺.

N-(3-((6-amino-5-(1-(3-(dimethylamino)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A212)

N-(3-((6-amino-5-(1-(3-(dimethylamino)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,N,N-dimethyl-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)aniline,and acryloyl chloride using methods A, C, and F. HPLC: 100%. MS: m/z=456[M+H]⁺. ¹H-NMR (DMSO-d₆) δ 10.20 (s, 1H), 8.11 (s, 1H), 7.99 (s, 1H),7.71 (s, 1H), 7.49 (s, 1H), 7.41 (d, 1H), 7.31 (t, 1H), 7.12 (t, 1H),6.80 (d, 1H), 6.64-6.56 (m, 5H), 6.42 (dd, 1H), 6.25 (d, 1H), 5.76 (d,1H), 5.28 (s, 2H), 2.83 (s, 6H).

N-(3-((6-amino-5-(4-(3-cyanophenoxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A213)

N-(3-((6-amino-5-(4-(3-cyanophenoxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from 5,6-dichloropyrimidin-4-amine, 3-aminophenol,3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile,and acryloyl chloride using methods A, C, and F. HPLC: 98%. MS: m/z=450[M+H]⁺. ¹H-NMR (DMSO-d₆) b 10.21 (s, 1H), 8.07 (s, 0.5H), 7.61-7.57 (m,3.5H), 7.49-7.43 (m, 4H), 7.38 (d, 1H), 7.30 (t, 1H), 7.19 (d, 2H), 6.79(d, 1H), 6.57 (broad s, 1.5H), 6.41 (dd, 1H), 6.25 (d, 1H), 5.76 (d,1H).

3-(4-(4-(((1-acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile(A214)

3-(4-(4-(((1-acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrilewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate,3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile,and acryloyl chloride using methods B, C, D, and F. HPLC: 100%. MS:m/z=455 [M+H]⁺. ¹H-NMR (DMSO-d₆) δ 7.96 (s, 1H), 7.63-7.56 (m, 3H),7.50-7.45 (m, 1H), 7.29-7.19 (m, 4H), 6.78 (dd, 1H), 6.06 (d, 1H), 5.63(d, 1H), 5.58-5.42 (m, 3H), 4.36 (d, 1H), 4.00 (d, 1H), 3.15 (t, 2H),2.96 (t, 1H), 2.58 (t, 1H), 1.90-1.78 (m, 1H), 1.69-1.55 (m, 2H),1.04-0.87 (m, 2H).

1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)but-2-yn-1-one(A215)

1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)but-2-yn-1-onewas prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid,(3S,4S)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate andbut-2-ynoic acid with method S1, S2, S3, S4A. Yield 41.3%. ¹H NMR(CD₃OD) δ 8.26 (s, 1H), 7.14-7.40 (m, 9H), 4.28-4.48 (m, 2H), 3.66 (m,1H), 3.52 (m, 1H), 3.01 (m, 1H), 2.60 (m, 1H), 2.0 (m, 3H), 1.75 (m,2H), 1.20 (m, 1H). HPLC PURITY: 99%, MS: m/z=458[M+H]+

1-acryloyl-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidine-4-carboxylicacid (A216)

1-acryloyl-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidine-4-carboxylicacid was prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronicacid,4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acidcarboxylate and acrylic acid with method S1, S2, S3, S4A. Yield 35.9%.¹H NMR (CD₃OD) δ 8.26 (s, 1H), 7.14-7.40 (m, 9H), 6.73 (m, 1H), 6.21 (d,1H), 5.73 (d, 1H), 4.25 (d, 1H), 3.89 (d, 1H), 3.73 (s, 2H), 3.02 (t,1H), 2.08 (t, 2H), 1.45 (m, 2H). HPLC PURITY: 94%, MS: m/z=474[M+H]+

(E)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-1-(4-(dimethylamino)but-2-enoyl)piperidine-4-carboxylicacid (A217)

(E)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-1-(4-(dimethylamino)but-2-enoyl)piperidine-4-carboxylicacid was prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronicacid,4-(aminomethyl)-1-(tert-butoxycarbonyl) piperidine-4-carboxylicacid carboxylate and (E)-4-(dimethylamino)but-2-enoic acid hydrochloridewith method S1, S2, S3, S4A. Yield 15.6%. ¹H NMR (CD₃OD) δ 8.26 (s, 1H),7.14-7.40 (m, 9H), 6.94 (d, 1H), 6.66 (m, 1H), 4.25 (d, 1H), 3.97 (m,3H), 3.73 (s, 2H), 3.31 (m, 1H), 3.08 (t, 1H), 2.08 (t, 2H), 1.49 (m,2H). HPLC PURITY: 94%, MS: m/z=531 [M+H]+

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(3-fluoroazetidin-1-yl)but-2-en-1-one(A218)

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(3-fluoroazetidin-1-yl)but-2-en-1-onewas prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid,tert-butyl 4-(aminomethyl)piperidine-1-carboxylate and(E)-4-(3-fluoroazetidin-1-yl)but-2-enoic acid with method S1, S2, S3,S4A. Yield 6.0%. ¹H NMR (CD₃OD) δ 8.04 (s, 1H), 7.19-7.47 (m, 9H), 6.57(m, 2H), 5.22 (m, 1H), 4.50 (d, 1H), 4.10 (d, 1H), 3.79 (m, 2H), 3.50(m, 3H), 3.13 (m, 1H), 2.63 (t, 1H), 1.87 (m, 1H), 1.76 (t, 2H), 1.15(m, 2H). HPLC PURITY: 99%, MS: m/z=517[M+H]+

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(3,3-difluoroazetidin-1-yl)but-2-en-1-one(A219)

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(3,3-difluoroazetidin-1-yl)but-2-en-1-onewas prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenyl boronicacid, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate and(E)-4-(3,3-difluoroazetidin-1-yl)but-2-enoic acid with method S1, S2,S3, S4A. Yield 19.3%. ¹H NMR (CD₃OD) δ 8.26 (s, 1H), 7.19-7.47 (m, 9H),6.78 (d, 1H), 6.14 (m, 1H), 4.50 (d, 1H), 4.41 (t, 3H), 4.09 (d, 1H),3.89 (d, 1H), 3.38 (m, 2H), 3.13 (m, 1H), 2.72 (t, 1H), 1.91 (m, 1H),1.76 (t, 2H), 1.28 (m, 2H). HPLC PURITY: 99%, MS: m/z=535[M+H]+

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(pyrrolidin-1-yl)but-2-en-1-one(A220)

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(pyrrolidin-1-yl)but-2-en-1-onewas prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid,tert-butyl 4-(aminomethyl)piperidine-1-carboxylate and(E)-4-(pyrrolidin-1-yl)but-2-enoic acid with method S1, S2, S3, S4A.Yield 9.1%. ¹H NMR (CD₃OD) δ 8.31 (m, 2H), 7.19-7.47 (m, 9H), 6.92 (d,1H), 6.63 (m, 1H), 4.54 (d, 1H), 4.07 (d, 1H), 4.01 (d, 2H), 3.64 (s,1H), 3.12 (t, 2H), 2.75 (t, 1H), 2.20 (s, 1H), 2.03 (s, 1H), 1.75 (t,2H), 1.11 (t, 2H). HPLC PURITY: 91%, MS: m/z=513[M+H]+

1-(6-((6-amino-5-(4-(pyridin-3-yloxy)phenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one(A221)

1-(6-((6-amino-5-(4-(pyridin-3-yloxy)phenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-onewas prepared 5,6-dichloropyrimidin-4-amine, (4-(pyridin-3-yloxy)phenyl)boronic acid, tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylateand acrylic acid with method S1, S2, S3, S4A. Yield 21.2%. ¹H NMR(CD₃OD) δ 8.31 (m, 2H), 8.13 (s, 1H), 7.52 (m, 1H), 6.97 (m, 1H), 7.41(d, 2H), 7.19 (m, 2H), 6.25 (m, 2H), 5.75 (m, 1H), 5.24 (m, 1H), 4.21(d, 2H), 4.03 (d, 2H), 2.72 (m, 2H), 2.25 (m, 2H). HPLC PURITY: 99%, MS:m/z=430[M+H]+

(E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(3-fluoroazetidin-1-yl)but-2-en-1-one(A222)

(E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(3-fluoroazetidin-1-yl)but-2-en-1-onewas prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid,tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate and(E)-4-(3-fluoroazetidin-1-yl)but-2-enoic acid with method S1, S2, S3,S4A. Yield 1.7%. ¹H NMR (CD₃OD) δ 8.28 (s, 1H), 7.10-7.47 (m, 9H), 6.62(m, 1H), 6.40 (t, 1H), 5.41 (m, 1H), 5.25 (m, 1H), 4.27 (d, 2H), 4.04(m, 4H), 2.74 (m, 2H), 2.27 (m, 2H). HPLC PURITY: 99%, MS: m/z=516[M+H]+

(E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(3,3-difluoroazetidin-1-yl)but-2-en-1-one(A223)

(E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(3,3-difluoroazetidin-1-yl)but-2-en-1-onewas prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid,tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate and(E)-4-(3,3-difluoroazetidin-1-yl)but-2-enoic acid with method S1, S2,S3, S4A. Yield 2.7%. ¹H NMR (CD₃OD) δ 8.31 (s, 1H), 7.10-7.47 (m, 9H),6.60 (m, 1H), 6.40 (t, 1H), 5.25 (m, 1H), 4.54 (qt, 4H), 4.27 (d, 2H),4.08 (s, 1H), 4.00 (m, 3H), 2.74 (m, 2H), 2.27 (m, 2H). HPLC PURITY:95%, MS: m/z=534[M+H]⁺

(E)-N-(1,3-cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamide(A224)

(E)-N-(1,3-cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamidewas prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid,tert-butyl(1,3-cis-3-aminocyclobutyl)carbamate and(E)-4-(dimethylamino)but-2-enoic acid hydrochloride with method S1, S2,S3, S4A. Yield 19.4%. ¹H NMR (CD₃OD) δ 8.31 (s, 1H), 7.10-7.47 (m, 9H),6.60 (m, 1H), 6.40 (t, 1H), 5.25 (m, 1H), 4.54 (qt, 4H), 4.27 (d, 2H),4.08 (s, 1H), 4.00 (m, 6H), 2.74 (m, 2H), 2.27 (m, 2H) HPLC. PURITY:99%, MS: m/z=459[M+H]+

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one(A225)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-onewas prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid,tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate and acrylicacid with method S1, S2, S3, S4A. Yield 16.1%. ¹H NMR (CD₃OD) δ 8.26 (s,1H), 7.14-7.40 (m, 9H), 6.73 (m, 1H), 6.24 (d, 1H), 5.73 (d, 1H), 4.41(d, 1H), 4.00 (d, 1H), 3.74 (d, 2H), 3.44 (m, 1H), 3.02 (t, 1H), 1.73(m, 2H), 1.61 (m, 2H). HPLC PURITY: 94%, MS: m/z=448[M+H]+

(E)-1-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]octan-6-yl)-4-(dimethylamino)but-2-en-1-one(A226)

(E)-1-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]octan-6-yl)-4-(dimethylamino)but-2-en-1-onewas prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid,tert-butyl 2-amino-6-azaspiro[3.4]octane-6-carboxylate and(E)-4-(dimethylamino)but-2-enoic acid hydrochloride with method S1, S2,S3, S4A. Yield 5.4%. ¹H NMR (CD₃OD) δ 8.31 (s, 1H), 7.10-7.47 (m, 9H),6.75 (m, 2H), 3.97 (m, 2H), 3.65 (m, 1H), 3.50 (m, 1H), 2.92 (m, 6H),2.38 (m, 2H), 2.12 (m, 2H), 2.0 (t, 1H), 1.80 (m, 2H), 1.62 (m, 2H).HPLC PURITY: 98%, MS: m/z=499[M+H]+

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)-4-(dimethylamino)but-2-en-1-one(A227)

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)-4-(dimethylamino)but-2-en-1-onewas prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid,tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate and(E)-4-(dimethylamino)but-2-enoic acid hydrochloride with method S1, S2,S3, S4A. Yield 15.9%. ¹H NMR (CD₃OD) δ 8.26 (s, 1H), 7.14-7.40 (m, 9H),6.93 (d, 1H), 6.74 (m, 1H), 4.47 (d, 1H), 3.98 (m, 3H), 3.75 (d, 2H),3.41 (t, 1H), 3.03 (t, 1H), 2.97 (m, 6H), 1.81 (m, 2H), 1.62 (m, 2H).HPLC PURITY: 99%, MS: m/z=505[M+H]+

(E)-N-(1,3-trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamide(A228)

(E)-N-((1,3-trans)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamidewas prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid,tert-butyl(1,3-trans-3-aminocyclobutyl)carbamate and(E)-4-(dimethylamino)but-2-enoic acid hydrochloride with method S1, S2,S3, S4A. Yield 23.6%. ¹H NMR (CD₃OD) δ 8.25 (s, 1H), 7.10-7.47 (m, 9H),6.73 (m, 1H), 6.40 (d, 1H), 4.26 (m, 1H), 3.92 (m, 2H), 2.96 (s, 6H),1.79 (m, 2H), 1.67 (m, 2H) HPLC PURITY: 99%, MS: m/z=459[M+H]+

N-(1,3-cis-3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide(A229)

N-(1,3-cis-3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclobutyl)acrylamidewas prepared 5,6-dichloropyrimidin-4-amine,(1-benzyl-1H-pyrazol-4-yl)boronic acid,tert-butyl(1,3-cis-3-aminocyclobutyl) carbamate and acrylic acid withmethod S1, S2, S3, S4A. Yield 8.2%. ¹H NMR (CD₃OD) δ 8.25 (s, 1H), 7.80(s, 1H), 7.59 (s, 1H), 7.38 (m, 5H), 6.24 (m, 2H), 5.61 (d, 1H), 5.45(s, 2H), 4.37 (m, 1H), 4.03 (m, 1H), 2.74 (m, 2H), 2.02 (m, 2H). HPLCPURITY: 95%, MS: m/z=390[M+H]+

(E)-N-(1,3-cis-3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamide(A230)

(E)-N-(1,3-cis-3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamidewas prepared 5,6-dichloropyrimidin-4-amine,(1-benzyl-1H-pyrazol-4-yl)boronic acid,tert-butyl(1,3-cis-3-aminocyclobutyl) carbamate and(E)-4-(dimethylamino)but-2-enoic acid hydrochloride with method S1, S2,S3, S4A. Yield 31.2%. ¹H NMR (CD₃OD) δ 7.95 (s, 1H), 7.77 (s, 1H), 7.38(m, 5H), 6.74 (m, 1H), 6.01 (d, 1H), 5.45 (s, 2H), 4.25 (m, 1H), 4.08(m, 1H), 3.09 (d, 2H), 2.74 (m, 2H), 2.27 (m, 2H). HPLC PURITY: 91%, MS:m/z=447[M+H]+

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-3-phenylprop-2-en-1-one(A231)

(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-3-phenylprop-2-en-1-onewas prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid,tert-butyl 4-(aminomethyl)piperidine-1-carboxylate and cinnamic acidwith method S1, S2, S3, S4A. Yield 45.4%. ¹H NMR (CD₃OD) δ 8.04 (s, 1H),7.19-7.47 (m, 14H), 4.55 (d, 1H), 4.25 (d, 1H), 3.42 (d, 2H), 3.14 (t,1H), 2.75 (t, 1H), 2.00 (m, 1H), 1.76 (t, 2H), 1.15 (m, 2H). HPLCPURITY: 98%, MS: m/z=506[M+H]+

1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-(dimethylamino)propan-1-one(A232)

1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-(dimethylamino)propan-1-onewas prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid,(3S,4S)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate and3-(dimethylamino)propanoic acid with method S1, S2, S3, S4A. Yield17.3%. ¹H NMR (CD₃OD) δ 8.26 (s, 1H), 7.14-7.40 (m, 9H), 4.48 (dd, 1H),3.89 (m, 1H), 3.66 (m, 1H), 3.28 (m, 1H), 3.01 (m, 1H), 2.61 (m, 4H),2.44 (t, 1H), 2.25 (s, 6H), 1.75 (m, 2H), 1.20 (m, 1H). HPLC PURITY:92%, MS: m/z=491[M+H]+

1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-(piperidin-1-yl)propan-1-one(A233)

1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-(piperidin-1-yl)propan-1-onewas prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid,(3S,4S)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate and3-(piperidin-1-yl)propanoic acid with method S1, S2, S3, S4A. Yield24.2%. ¹H NMR (CD₃OD) δ 8.26 (s, 1H), 7.14-7.40 (m, 9H), 4.48 (dd, 1H),3.89 (t, 1H), 3.67 (t, 1H), 3.28 (m, 1H), 3.00 (m, 1H), 2.31-2.61 (m,8H), 1.75 (m, 5H), 1.49 (s, 2H), 1.20 (m, 1H). HPLC PURITY: 99%, MS:m/z=530[M+H]+

1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-morpholinopropan-1-one(A234)

1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-morpholinopropan-1-onewas prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid,(3S,4S)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate and3-morpholinopropanoic acid with method S1, S2, S3, S4A. Yield 30.5%. ¹HNMR (CD₃OD) δ 8.26 (s, 1H), 7.14-7.40 (m, 9H), 4.48 (dd, 1H), 3.88 (t,1H), 3.66 (m, 5H), 3.28 (m, 1H), 3.00 (m, 1H), 2.33-2.61 (m, 9H), 1.49(s, 2H), 1.20 (m, 1H). HPLC PURITY: 99%, MS: m/z=533[M+H]+

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)-3-(piperidin-1-yl)propan-1-one(A235)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)-3-(piperidin-1-yl)propan-1-onewas prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid,tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate and3-(piperidin-1-yl)propanoic acid with method S1, S2, S3, S4A. Yield23.4%. ¹H NMR (CD₃OD) δ 8.26 (s, 1H), 7.14-7.40 (m, 9H), 4.29 (d, 1H),3.80 (d, 1H), 3.62 (dd, 2H), 3.00 (m, 1H), 2.60-2.77 (m, 7H), 1.78 (m,2H), 1.69 (m, 5H), 1.52 (m, 2H). HPLC PURITY: 99%, MS: m/z=533[M+H]+

(E)-N-(1,3-cis-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamide(A236)

(E)-N-(1,3-cis-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamidewas prepared 5,6-dichloropyrimidin-4-amine,(4-(3-(trifluoromethyl)phenoxy)phenyl)boronic acid,tert-butyl(1,3-cis-3-aminocyclobutyl)carbamate and(E)-4-(dimethylamino)but-2-enoic acid hydrochloride with method S1, S2,S3, S4A. Yield 17.1%. ¹H NMR (CDCl₃) δ 8.26 (s, 1H), 7.18-7.53 (m, 8H),6.74 (m, 1H), 6.49 (m, 1H), 4.58 (m, 2H), 4.26 (m, 1H), 4.13 (m, 1H),3.58 (m, 2H), 2.69 (m, 6H), 1.74 (m, 2H). HPLC PURITY: 99%, MS:m/z=527[M+H]+

N-(1,3-trans-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide(A237)

N-(1,3-trans-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamidewas prepared 5,6-dichloropyrimidin-4-amine,(4-(3-(trifluoromethyl)phenoxy)phenyl)boronic acid, tert-butyl(1,3-trans-3-aminocyclobutyl)carbamate and acrylic acid with method S1,S2, S3, S4A. Yield 22.8%. ¹H NMR (CDCl₃) δ 8.26 (s, 1H), 7.18-7.53 (m,8H), 6.74 (d, 1H), 6.27 (m, 1H), 5.71 (d, 1H), 5.25 (m, 1H), 4.50 (m,1H), 2.50 (m, 2H), 2.28 (m, 2H). HPLC PURITY: 99%, MS: m/z=470[M+H]+

N-(1,3-cis-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide(A238)

N-(1,3-cis-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamidewas prepared 5,6-dichloropyrimidin-4-amine,(4-(3-(trifluoromethyl)phenoxy)phenyl)boronic acid,tert-butyl(1,3-cis-3-aminocyclobutyl)carbamate and acrylic acid withmethod S1, S2, S3, S4A. Yield 22.1%. ¹H NMR (CDCl₃) δ 8.23 (s, 1H),7.18-7.53 (m, 8H), 6.25 (d, 1H), 6.04 (m, 1H), 5.66 (d, 1H), 4.42 (m,1H), 4.03 (m, 1H), 2.81 (m, 2H), 2.02 (m, 2H). HPLC PURITY: 98%, MS:m/z=470[M+H]+

1-acryloyl-4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidine-4-carboxylicacid (A239)

1-acryloyl-4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidine-4-carboxylicacid was prepared 5,6-dichloropyrimidin-4-amine,(4-(3-(trifluoromethyl)phenoxy)phenyl)boronic acid,4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid andacrylic acid with method S1, S2, S3, S4A. Yield 11.2%. ¹H NMR (DMSO-d₆)δ 8.31 (s, 1H), 7.25-7.75 (m, 8H), 7.03 (br., 2H), 6.77 (m, 1H), 6.62(s, 1H), 6.04 (d, 1H), 5.60 (d, 1H), 4.12 (m, 1H), 3.83 (m, 1H), 2.75(m, 1H), 1.91 (m, 2H), 1.28 (m, 2H). HPLC PURITY: 98%, MS: m/z=542[M+H]+

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-fluorophenyl)acrylamide(A240)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-fluorophenyl)acrylamidewas prepared from6-(3-amino-2-fluorophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine usingMethod F (82% yield). HPLC: 99%, RT=4.434 min. MS: m/z=433 [M+H]⁺,RT=2.36 min. ¹H-NMR (DMSO-d₆) δ 10.02 (s, 1H), 8.04 (s, 1H), 7.80 (t,1H), 7.43-7.38 (m, 4H), 7.15 (q, 2H), 7.15 (q, 2H), 7.09 (d, 4H), 7.03(t, 1H), 6.69 (broad s, 1.5H), 6.57 (dd, 1H), 6.26 (d, 1H), 5.77 (d,1H).

N-(3-(4-amino-6-((4-phenoxyphenyl)amino)pyrimidin-5-yl)phenyl)acrylamide(A241)

N-(3-(4-amino-6-((4-phenoxyphenyl)amino)pyrimidin-5-yl)phenyl)acrylamidewas prepared from5-(3-aminophenyl)-N4-(4-phenoxyphenyl)pyrimidine-4,6-diamine usingMethod E (21% yield). HPLC: 98%, RT=3.975 min. MS: m/z=424 [M+H]⁺,RT=2.51 min. ¹H-NMR (DMSO-d₆) δ 10.26 (s, 1H), 8.42 (s, 1H), 8.20 (s,1H), 7.77 (d, 1H), 7.60) s, 1H), 7.45 (t, 1H), 7.32 (t, 2H), 7.25 (d,2H), 7.06 (t, 1H), 7.00 (d, 1H), 6.92-6.88 (m, 5H), 6.40 (dd, 1H), 6.21(d, 1H), 5.71 (d, 1H).

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A242)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine using Method E(20% yield). HPLC: 97%, RT=4.264 min. MS: m/z=425 [M+H]⁺, RT=4.22 min.¹H-NMR (DMSO-d₆) δ 10.14 (s, 1H), 8.00 (s, 1H), 7.41 (s, 1H), 7.36-7.30(m, 5H), 7.22 (t, 1H), 7.09 (t, 1H), 7.03-7.01 (m, 4H), 6.71 (d, 1H),6.53 (broad s, 2H), 6.34 (dd, 1H), 6.18 (d, 1H), 5.69 (d, 1H).

N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide (A243)

N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide wasprepared from 3-(3-aminophenyl)-4-(4-phenoxyphenoxy)pyridin-2-amineusing Method F (56% yield).). HPLC: 99%, RT=4.196 min. MS: m/z=424[M+H]⁺, RT=2.09 min. ¹H-NMR (DMSO-d₆) δ□ 10.24 (s, 1H), 7.89 (d, 1H),7.75 (s, 1H), 7.65 (d, 1H), 7.43 (t, 1H), 7.33 (t, 2H), 7.15-7.08 (m,6H), 7.02 (d, 2H), 6.96 (d, 2H), 6.40 (dd, 1H), 6.30 (d, 1H), 6.20 (d,1H), 5.71 (d, 1H).

N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide(A244)

N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide wasprepared from 4-(3-aminophenoxy)-3-(4-phenoxyphenyl)pyridin-2-amineusing Method F (52% yield). HPLC: 99%, RT=4.182 min. MS: m/z=424 [M+H]⁺,RT=2.08 min. ¹H-NMR (DMSO-d₆) □□ 10.35 (s, 1H), 7.93 (d, 1H), 7.65 (s,1H), 7.43-7.37 (m, 6H), 7.28 (s, 2H), 7.18 (t, 1H), 7.12-7.08 (m, 4H),6.86 (d, 1H), 6.40 (dd, 1H), 6.33 (d, 1H), 6.24 (d, 1H), 5.77 (d, 1H).

N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)acrylamide(A245)

N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)acrylamide wasprepared from 5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amineusing Method E (24% yield). HPLC: 94%, RT=4.298 min. MS: m/z=425 [M+H]⁺,RT=2.16 min. ¹H-NMR (DMSO-d₆) δ 10.10 (s, 1H), 8.08 (s, 1H), 7.71 (s,2H), 7.41 (t, 1H), 7.37 (t, 2H), 7.13-6.97 (m, 8H), 6.53 (broad s, 2H),6.44 (dd, 1H), 6.25 (d, 1H), 5.75 (d, 1H).

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamide(A246)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamidewas prepared from6-(5-amino-2-fluorophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine usingMethod F (6% yield). HPLC: 99%, RT=4.470 min. MS: m/z=443 [M+H]⁺,RT=2.38 min. ¹H-NMR (DMSO-d₆) δ 10.18 (s, 1H), 7.96 (s, 1H), 7.58 (d,1H), 7.36-7.32 (m, 5H), 7.20 (t, 1H), 7.10 (t, 1H), 7.05-7.03 (m, 4H),6.51 (broad s, 2H), 6.32 (dd, 1H), 6.18 (d, 1H), 5.70 (d, 1H).

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one(A247)

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-onewas prepared from(R)-5-(4-phenoxyphenyl)-N4-(piperidin-3-yl)pyrimidine-4,6-diamine usingMethod F (42% yield). HPLC: 97%, RT=3.713 min. MS: m/z=416 [M+H]⁺,RT=1.76 min.

(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-(dimethylamino)but-2-enamide(A248)

(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-(dimethylamino)but-2-enamidewas prepared from5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine and(E)-4-(dimethylamino)but-2-enoic acid hydrochloride using Method E (26%yield). HPLC: 97%, RT=3.608 min. MS: m/z=482 [M+H]⁺, RT=3.57 min. ¹H-NMR(DMSO-d₆), δ 10.33 (s, 1H), 9.66 (s, 1H), 8.01 (s, 1H), 7.66-7.64 (m,2H), 7.38 (t, 1H), 7.32 (t, 2H), 7.11-6.92 (m, 8H), 6.68 (m, 1H), 6.41(m, 3H), 3.88 (m, 2H), 2.73 (s, 6H).

N-(3-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A249)

N-(3-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from6-(3-aminophenoxy)-5-(4-(benzyloxy)phenyl)pyrimidin-4-amine using MethodE (16% yield). HPLC: 100%, RT=4.251 min. MS: m/z=439 [M+H]⁺, RT=2.12min. ¹H-NMR (DMSO-d₆), δ 10.18 (s, 1H), 8.04 (d, 1H), 7.47-7.25 (m,10H), 7.10 (d, 2H), 6.74 (d, 1H), 6.49 (broad s, 2H), 6.39 (dd, 1H),6.23 (d, 1H), 5.75 (d, 1H), 5.11 (s, 2H).

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A250)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl4-(aminomethyl)piperidine-1-carboxylate, (4-phenoxyphenyl)boronic acidand acryloyl chloride in four steps according to Scheme 2 (using MethodB/I, Method C, Method D, and Method F). HPLC purity 97%, RT=3.665 min;MS: m/z=430 [M+H]⁺, RT=1.53 min. ¹H-NMR (DMSO-d₆) δ 7.93 (s, 1H), 7.40(t, 2H), 7.21-7.08 (m, 8H), 6.76 (dd, 1H), 6.04 (d, 1H), 5.61 (d, 1H),5.43 (s, 2H), 4.34 (d, 1H), 3.98 (d, 1H), 3.12 (t, 2H), 2.95 (t, 1H),2.56 (t, 1H), 1.81 (m, 1H), 1.59 (m, 2H), 0.92 (m, 2H).

N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2,4-difluorophenyl)acrylamide(A251)

N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2,4-difluorophenyl)acrylamidewas prepared from6-(5-amino-2,4-difluorophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amineusing Method F (10% yield). HPLC: 99%, RT=4.569 min. MS: m/z=461 [M+H]⁺,RT=2.42 min. ¹H-NMR (DMSO-d₆), δ 10.02 (s, 1H), 8.01 (s, 1H), 7.87 (t,1H), 7.48 (t, 1H), 7.42-7.38 (m, 4H), 7.15 (t, 1H), 7.10-7.07 (m, 4H),6.56 (dd, 1H), 6.55 (broad s, 2H), 6.24 (d, 1H), 5.77 (d, 1H).

(E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide(A252)

(E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamidewas prepared from6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and(E)-4-(dimethylamino)but-2-enoic acid hydrochloride using Method E (22%yield). HPLC: 98%, RT=3.556 min. MS: m/z=482 [M+H]⁺, RT=3.53 min. ¹H-NMR(DMSO-d₆) δ 10.34 (s, 1H), 9.73 (s, 1H), 8.04 (s, 1H), 7.45 (s, 1H),7.41-7.36 (m, 5H), 7.29 (t, 1H), 7.15 (t, 1H), 7.09-7.06 (m, 4H), 6.78(d, 1H), 6.74-6.68 (m, 1H), 6.50 (broad s, 2H), 6.41 (d, 1H), 3.93-3.92(m, 2H), 2.78 (s, 6H).

1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one(A253)

1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-onewas prepared from5-(4-phenoxyphenyl)-N4-(piperidin-3-yl)pyrimidine-4,6-diamine usingMethod F (27% yield). HPLC: 99%, RT=3.737 min. MS: m/z=416 [M+H]⁺,RT=1.88 min.

N-(3-((6-amino-5-(4-((2-methoxybenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A254)

N-(3-((6-amino-5-(4-((2-methoxybenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from6-(3-aminophenoxy)-5-(4-((2-methoxybenzyl)oxy)phenyl)pyrimidin-4-amineusing Method F (58% yield). HPLC: 99%, RT=4.290 min. MS: m/z=469 [M+H]⁺,RT=2.32 min. ¹H-NMR (DMSO-d₆) 1H), 8.14 (s, 1H), 7.50 (s, 1H), 7.44-7.30(m, 6H), 7.13 (d, 2H), 7.08 (d, 1H), 6.99 (t, 1H), 6.79 (m, 3H), 6.42(dd, 1H), 6.27 (d, 1H), 5.78 (d, 1H), 5.10 (s, 2H), 3.84 (s, 3H).

N-(3-((5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide (A255)

N-(3-((5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide wasprepared from 3-((5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)aniline usingMethod F (86% yield). HPLC: 97%, RT=5.029 min. MS: m/z=410 [M+H]⁺,RT=2.57 min. ¹H-NMR (DMSO-d₆) 1H), 8.78 (s, 1H), 8.69 (s, 1H), 7.76 (d,2H), 7.66 (s, 1H), 7.45-7.36 (m, 4H), 7.18 (t, 1H), 7.13-7.08 (m, 4H),6.96 (d, 1H), 6.41 (dd, 1H), 6.24 (d, 1H), 5.76 (d, 1H).

N-(3-((6-amino-5-(4-(benzyloxy)-3-methoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A256)

N-(3-((6-amino-5-(4-(benzyloxy)-3-methoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from6-(3-aminophenoxy)-5-(4-(benzyloxy)-3-methoxyphenyl)pyrimidin-4-amineusing Method F (53% yield). HPLC: 100%, RT=4.133 min. MS: m/z=469[M+H]⁺, RT=2.19 min. ¹H-NMR (DMSO-d₆) δ 10.13 (s, 1H), 7.99 (s, 1H),7.41-7.20 (m, 8H), 7.07 (d, 1H), 6.93 (s, 1H), 6.85 (d, 1H), 6.71 (d,1H), 6.50 (broad s, 2H), 6.34 (dd, 1H), 6.17 (d, 1H), 5.69 (d, 1H), 5.03(s, 2H), 3.71 (s, 3H).

N-(3-((6-amino-5-(4-(benzyloxy)-2,3-difluorophenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A257)

N-(3-((6-amino-5-(4-(benzyloxy)-2,3-difluorophenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from6-(3-aminophenoxy)-5-(4-(benzyloxy)-2,3-difluorophenyl)pyrimidin-4-amineusing Method F (37% yield). HPLC: 100%, RT=4.611 min. MS: m/z=475[M+H]⁺, RT=2.39 min. ¹H-NMR (DMSO-d₆ 1H), b 10.14 (s, 1H), 8.02 (s, 1H),7.43-7.28 (m, 7H), 7.22 (t, 1H), 7.12 (quintet, 2H), 6.68 (m, 3H), 6.34(dd, 1H), 6.18 (d, 1H), 5.69 (d, 1H), 5.18 (s, 2H).

4-(4-(3-acrylamidophenoxy)-6-aminopyrimidin-5-yl)-N-phenylbenzamide(A258)

4-(4-(3-acrylamidophenoxy)-6-aminopyrimidin-5-yl)-N-phenylbenzamide wasprepared from4-(4-amino-6-(3-aminophenoxy)pyrimidin-5-yl)-N-phenylbenzamide usingMethod F (29% yield). HPLC: 98%, RT=3.775 min. MS: m/z=452 [M+H]⁺,RT=1.96 min. ¹H-NMR (DMSO-d₆) δ 10.22 (s, 1H), 10.16 (s, 1H), 8.04 (s,1H), 7.98 (d, 2H), 7.72 (d, 2H), 7.52 (d, 2H), 7.44 (s, 1H), 7.30-7.22(m, 4H), 7.04 (t, 1H), 6.73 (d, 1H), 6.63 (broad s, 2H), 6.34 (dd, 1H),6.18 (d, 1H), 5.70 (d, 1H).

N-(3-((6-amino-5-(6-(benzyloxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A259)

N-(3-((6-amino-5-(6-(benzyloxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from6-(3-aminophenoxy)-5-(6-(benzyloxy)pyridin-3-yl)pyrimidin-4-amine usingMethod F (38% yield). HPLC: 99%, RT=4.138 min. MS: m/z=440 [M+H]⁺,RT=2.20 min. ¹H-NMR (DMSO-d₆) δ 10.19 (s, 1H), 8.19 (s, 1H), 8.06 (s,1H), 7.74 (d, 1H), 7.46-7.26 (m, 8H), 6.97 (d, 1H), 6.77 (d, 1H), 6.69(broad s, 2H), 6.39 (dd, 1H), 6.23 (d, 1H), 5.74 (d, 1H), 5.36 (s, 2H).

N-(3-((6-amino-5-(4-((3-fluorobenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A260)

N-(3-((6-amino-5-(4-((3-fluorobenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from6-(3-aminophenoxy)-5-(4-((3-fluorobenzyl)oxy)phenyl)pyrimidin-4-amineusing Method E (13% yield). HPLC: 99%, RT=4.334 min. MS: m/z=457 [M+H]⁺,RT=2.17 min. ¹H-NMR (DMSO-d₆), δ 10.18 (s, 1H), 8.04 (s, 1H), 7.46-7.41(m, 2H), 7.36-7.25 (m, 6H), 7.15 (t, 1H), 7.10 (d, 2H), 6.75 (d, 1H),6.50 (broad s, 2H), 6.39 (dd, 1H), 6.23 (d, 1H), 5.74 (d, 1H), 5.14 (s,2H).

N-(3-((6-amino-2′-(benzyloxy)-[5,5′-bipyrimidin]-4-yl)oxy)phenyl)acrylamide(A261)

N-(3-((6-amino-2′-(benzyloxy)-[5,5′-bipyrimidin]-4-yl)oxy)phenyl)acrylamidewas prepared from6-(3-aminophenoxy)-2′-(benzyloxy)-[5,5′-bipyrimidin]-4-amine usingMethod F (46% yield). HPLC: 99%, RT=3.953 min. MS: m/z=441 [M+H]⁺,RT=2.04 min. ¹H-NMR (DMSO-d₆) 1H), 8.64 (s, 2H), 8.08 (s, 1H), 7.48-7.26(m, 8H), 6.88 (broad s, 2H), 6.79 (d, 1H), 6.39 (dd, 1H), 6.23 (d, 1H),5.74 (d, 1H), 5.42 (s, 2H).

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one(A262)

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-onewas prepared from5-(4-phenoxyphenyl)-N4-(pyrrolidin-3-ylmethyl)pyrimidine-4,6-diamineusing Method F (26% yield). HPLC: 97%, RT=3.570 min. MS: m/z=416 [M+H]⁺,RT=1.77 min.

1-(4-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one (A263)

1-(4-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-onewas prepared from6-(4-phenoxyphenoxy)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-amineusing Method F (41% yield). HPLC: 91%, RT=3.997 min. MS: m/z=415 [M+H]⁺,RT=2.00 min. ¹H-NMR (DMSO-d₆) δ 7.94 (s, 1H), 7.33 (t, 2H), 7.08-6.93(m, 7H), 6.82-6.68 (m, 3H), 6.07 (dd, 1H), 5.73 (d, 1H), 5.63 (t, 1H),4.15 (s, 1H), 4.07 (s, 1H), 3.71 (m, 2H), 2.25 (m, 2H).

N-(3-((6-amino-5-(4-((4-methoxybenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A264)

N-(3-((6-amino-5-(4-((4-methoxybenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from6-(3-aminophenoxy)-5-(4-((4-methoxybenzyl)oxy)phenyl)pyrimidin-4-amineusing Method F (35% yield). HPLC: 98%, RT=4.188 min. MS: m/z=469 [M+H]⁺,RT=2.25 min. ¹H-NMR (DMSO-d₆), δ 10.21 (s, 1H), 8.07 (s, 1H), 7.47 (s,1H), 7.42-7.28 (m, 6H), 7.12 (d, 2H), 6.97 (d, 2H), 6.78 (d, 1H), 6.50(broad s, 2H), 6.42 (dd, 1H), 6.26 (d, 1H), 5.77 (d, 1H), 5.05 (s, 2H),3.77 (s, 3H).

(E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-morpholinobut-2-enamide(A265)

(E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-morpholinobut-2-enamidewas prepared from6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and(E)-4-morpholinobut-2-enoic acid using Method E (19% yield). HPLC: 100%,RT=3.605 min. MS: m/z=524 [M+H]⁺, RT=3.59 min.

N-((1s,4s)-4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide(A266)

N-((1s,4s)-4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamidewas prepared from N4-((1s,4s)-4-aminocyclohexyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine usingMethod F (20% yield). HPLC: 100%, RT=3.712 min. MS: m/z=430 [M+H]⁺,RT=1.80 min.

N-(3-(4-((4-phenoxyphenyl)amino)pyridin-3-yl)phenyl)acrylamide (A267)

N-(3-(4-((4-phenoxyphenyl)amino)pyridin-3-yl)phenyl)acrylamide wasprepared from 3-(3-aminophenyl)-N-(4-phenoxyphenyl)pyridin-4-amine usingMethod E (13% yield). HPLC: 97%, RT=4.075 min. MS: m/z=408 [M+H]⁺,RT=2.04 min. ¹H-NMR (DMSO-d₆) δ 10.32 (s, 1H), 9.31 (s, 1H), 8.27 (s,1H), 8.23 (d, 1H), 7.89 (s, 1H), 7.77 (d, 1H), 7.50 (t, 1H), 7.41 (t,2H), 7.30 (d, 2H), 7.24 (d, 1H), 7.16 (t, 1H), 7.05 (dd, 4H), 6.98 (d,1H), 6.45 (dd, 1H), 6.27 (d, 1H), 5.77 (d, 1H).

N-(3-((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A268)

N-(3-((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from6-(3-aminophenoxy)-5-(6-phenoxypyridin-3-yl)pyrimidin-4-amine usingMethod F (70% yield). HPLC: 97%, RT=3.880 min. MS: m/z=426 [M+H]⁺,RT=2.03 min. ¹H-NMR (DMSO-d₆) δ 10.22 (s, 1H), 8.15 (s, 1H), 8.10 (s,1H), 7.87 (d, 1H), 7.48 (s, 1H), 7.40 (t, 2H), 7.36 (d, 1H), 7.28 (t,1H), 7.21 (t, 1H), 7.16 (d, 2H), 7.11 (d, 1H), 6.85 (broad s, 1H), 6.78(d, 1H), 6.39 (dd, 1H), 6.23 (d, 1H), 5.75 (d, 1H).

1-(3-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one(A269)

1-(3-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-onewas prepared from5-(4-(benzyloxy)phenyl)-N4-(piperidin-3-yl)pyrimidine-4,6-diamine usingMethod F (26% yield). HPLC: 100%, RT=3.701 min. MS: m/z=430 [M+H]⁺,RT=1.63 min.

N-(3-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide (A270)

N-(3-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide wasprepared from 3-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)aniline usingMethod E (36% yield). HPLC: 96%, RT=4.161 min. MS: m/z=409 [M+H]⁺,RT=4.15 min. ¹H-NMR (DMSO-d₆) δ 10.37 (s, 1H), 8.78 (s, 1H), 8.55 (d,1H), 7.72-7.70 (m, 3H), 7.46-7.40 (m, 4H), 7.18 (t, 1H), 7.10 (dd, 4H),7.03 (d, 1H), 6.97 (m, 1H), 6.41 (dd, 1H), 6.24 (d, 1H), 5.77 (d, 1H).

N-(3-((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A271)

N-(3-((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from4-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-2-amine using Method E(11% yield). HPLC: 99%, RT=4.256 min. MS: m/z=425 [M+H]⁺, RT=2.16 min.¹H-NMR (DMSO-d₆) δ 10.27 (s, 1H), 8.28 (s, 1H), 7.62-7.60 (m, 3H),7.45-7.35 (m, 4H), 7.20 (broad s, 2H), 7.15 (t, 1H), 7.05 (t, 4H), 6.96(d, 1H), 6.41 (dd, 1H), 6.25 (d, 1H), 5.76 (d, 1H).

3-(3-acrylamidophenyl)-4-(4-phenoxyphenoxy)picolinamide (A272)

3-(3-acrylamidophenyl)-4-(4-phenoxyphenoxy)picolinamide was preparedfrom 3-(3-aminophenyl)-4-(4-phenoxyphenoxy)picolinamide using Method E(29% yield). HPLC: 98%, RT=4.218 min. MS: m/z=452 [M+H]⁺, RT=2.15 min.

1-(3-(4-amino-6-((4-phenoxyphenyl)amino)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one(A273)

1-(3-(4-amino-6-((4-phenoxyphenyl)amino)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-onewas prepared fromN4-(4-phenoxyphenyl)-5-(1,2,5,6-tetrahydropyridin-3-yl)pyrimidine-4,6-diamineusing Method E (20% yield). HPLC: 97%, RT=3.813 min. MS: m/z=414 [M+H]⁺,RT=1.94 min.

(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-morpholinobut-2-enamide(A274)

(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-morpholinobut-2-enamidewas prepared from5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine and(E)-4-morpholinobut-2-enoic acid using Method E (15% yield). HPLC: 100%,RT=3.662 min. MS: m/z=524 [M+H]⁺, RT=3.66 min.

(S)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one(A275)

(S)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-onewas prepared from(S)-5-(4-phenoxyphenyl)-N4-(piperidin-3-yl)pyrimidine-4,6-diamine usingMethod F (42% yield). HPLC: 99%, RT=3.701 min. MS: m/z=416 [M+H]⁺,RT=1.75 min.

N-((1r,4r)-4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide(A276)

N-((1r,4r)-4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamidewas prepared from N4-((1r,4r)-4-aminocyclohexyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine usingMethod F (13% yield). HPLC: 100%, RT=3.690 min. MS: m/z=430 [M+H]⁺,RT=1.58 min.

N-(3-((6-amino-5-(4-fluoro-3-methoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A277)

N-(3-((6-amino-5-(4-fluoro-3-methoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from6-(3-aminophenoxy)-5-(4-fluoro-3-methoxyphenyl)pyrimidin-4-amine usingMethod E (13% yield). HPLC: 97%, RT=3.519 min. MS: m/z=381 [M+H]⁺,RT=1.77 min. ¹H-NMR (DMSO-d₆) δ 10.19 (s, 1H), 8.06 (s, 1H), 7.47 (s,1H), 7.35 (d, 1H), 7.29-7.25 (m, 2H), 7.17 (d, 1H), 6.94 (m, 1H), 6.77(d, 1H), 6.61 (broad s, 2H), 6.39 (dd, 1H), 6.23 (d, 1H), 5.74 (d, 1H),3.83 (s, 3H).

N-(3-((6-amino-5-(4-(2-hydroxypropan-2-yl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A278)

N-(3-((6-amino-5-(4-(2-hydroxypropan-2-yl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from2-(4-(4-amino-6-(3-aminophenoxy)pyrimidin-5-yl)phenyl)propan-2-ol usingMethod E (22% yield). HPLC: 97%, RT=3.038 min. MS: m/z=391 [M+H]⁺,RT=1.53 min. ¹H-NMR (DMSO-d₆) δ 10.19 (s, 1H), 8.06 (s, 1H), 7.55 (d,2H), 7.45 (s, 1H), 7.36-7.33 (m, 3H), 7.27 (t, 1H), 6.75 (d, 1H), 6.50(broad s, 2H), 6.39 (dd, 1H), 6.23 (d, 1H), 5.74 (d, 1H), 1.44 (s, 6H).

1-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one (A279)

1-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one was prepared from6-(4-phenoxyphenoxy)-5-(1,2,5,6-tetrahydropyridin-3-yl)pyrimidin-4-amineusing Method E (17% yield). HPLC: 100%, RT=4.065 min. MS: m/z=415[M+H]⁺, RT=2.07 min. ¹H-NMR (DMSO-D₆) δ 8.00 (s, 1H), 7.38 (t, 2H),7.14-7.08 (m, 3H), 7.00 (d, 4H), 6.88-6.70 (m, 3H), 6.09 (dd, 1H), 5.90(m, 1H), 5.68 (d, 0.5H), 5.58 (d, 0.5H), 8.16 (d, 2H), 3.73 (dt, 2H),2.25 (d, 2H).

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A280)

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from6-(4-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine using Method E(23% yield). HPLC: 97%, RT=4.191 min. MS: m/z=425 [M+H]⁺, RT=4.12 min.¹H-NMR (DMSO-d₆) δ 10.14 (s, 1H), 8.04 (s, 1H), 7.62 (d, 2H), 7.42-7.38(m, 4H), 7.15 (t, 1H), 7.08 (t, 4H), 7.02 (d, 2H), 6.54 (broad s, 2H),6.41 (dd, 1H), 6.24 (d, 1H), 5.74 (d, 1H).

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide (A281)

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide was preparedfrom 4-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline using Method G (17%yield). HPLC: 100%, RT=4.216 min. MS: m/z=409 [M+H]⁺, RT=3.29 min.¹H-NMR (DMSO-d₆) δ 9.89 (s, 1H), 9.01 (s, 1H), 8.85 (d, 1H), 8.30 (d,2H), 8.10 (d, 2H), 7.84 (t, 2H), 7.64 (d, 2H), 7.58 (t, 1H), 7.55 (d,2H), 7.48 (d, 2H), 7.25 (d, 1H), 6.92 (dd, 1H), 6.82 (d, 1H), 6.17 (d,1H).

(E)-4-(dimethylamino)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide(A282)

(E)-4-(dimethylamino)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamidewas prepared from 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and(E)-4-(dimethylamino)but-2-enoic acid using Method E (35% yield). HPLC:99%, RT=3.399 min. MS: m/z=466 [M+H]⁺, RT=3.37 min. ¹H-NMR (DMSO-d₆) δ10.52 (s, 1H), 8.70 (s, 1H), 8.56 (d, 1H), 8.04 (s, 1H), 7.74 (d, 1H),7.48 (t, 1H), 7.43-7.38 (m, 3H), 7.29-7.26 (d, 2H), 7.17-7.12 (m, 3H),7.05-6.99 (m, 3H), 6.74 (m, 1H), 6.48 (d, 1H), 3.94 (d, 2H), 2.79 (s,6H).

N-(3-(4-((4-phenoxyphenyl)amino)pyrimidin-5-yl)phenyl)acrylamide (A283)

N-(3-(4-((4-phenoxyphenyl)amino)pyrimidin-5-yl)phenyl)acrylamide wasprepared from 5-(3-aminophenyl)-N-(4-phenoxyphenyl)pyrimidin-4-amineusing Method E (19% yield). HPLC: 98%, RT=3.938 min. MS: m/z=409 [M+H]⁺,RT=1.93 min. ¹H-NMR (DMSO-d₆) δ 10.31 (s, 1H), 9.45 (s, 1H), 8.73 (s,1H), 8.29 (s, 1H), 7.87 (s, 1H), 7.80 (d, 1H), 7.51-7.49 (m, 3H), 7.38(t, 2H), 7.25 (d, 1H), 7.13 (t, 1H), 7.01-6.99 (m, 4H), 6.45 (dd, 1H),6.27 (d, 1H), 5.77 (d, 1H).

1-(3-((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one(A284)

1-(3-((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-onewas prepared from5-(4-phenoxyphenyl)-N-(piperidin-3-yl)pyrimidin-4-amine using Method F(19% yield). HPLC: 98%, RT=3.632 min. MS: m/z=401 [M+H]⁺, RT=1.52 min.

N-(3-((6-amino-5-(4-(pyrrolidine-1-carbonyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A285)

N-(3-((6-amino-5-(4-(pyrrolidine-1-carbonyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from(4-(4-amino-6-(3-aminophenoxy)pyrimidin-5-yl)phenyl)(pyrrolidin-1-yl)methanoneusing Method F (86% yield). HPLC: 99%, RT=3.121 min. MS: m/z=430 [M+H]⁺,RT=1.62 min. ¹H-NMR (DMSO-d₆) δ 10.15 (s, 1H), 8.04 (s, 1H), 7.53 (d,2H), 7.43-7.39 (m, 3H), 7.30 (d, 1H), 7.22 (t, 1H), 6.72 (d, 1H), 6.60(broad s, 2H), 6.34 (dd, 1H), 6.18 (d, 1H), 5.69 (d, 1H), 3.42-3.37 (m,4H), 1.77 (doublet of quintet, 4H).

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A286)

1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from5-(4-phenoxyphenyl)-N4-(piperidin-3-ylmethyl)pyrimidine-4,6-diamineusing Method F (40% yield).). HPLC: 99%, RT=3.733 min. MS: m/z=430[M+H]⁺, RT=1.72 min.

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide (A287)

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide was preparedfrom (4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine,triethylamine instead of N, N-diethylethanamine, THF instead ofmethylpyrrolidin-2-one and dichloromethane using Method G (23% yield).HPLC: 93%, RT=4.014 min. MS: m/z=423 [M+H]⁺, RT=3.16 min. ¹H-NMR(DMSO-d₆) δ 8.99 (s, 1H), 8.36 (d, 1H), 8.18 (s, 1H), 8.08 (d, 2H),7.89-7.83 (m, 4H), 7.65-7.48 (m, 7H), 7.25 (d, 1H), 6.80 (dd, 1H), 6.69(d, 1H), 6.05 (d, 1H), 4.98 (d, 2H).

1-(4′-(4-phenoxyphenoxy)-5,6-dihydro-[3,3′-bipyridin]-1(2H)-yl)prop-2-en-1-one(A288)

1-(4′-(4-phenoxyphenoxy)-5,6-dihydro-[3,3′-bipyridin]-1(2H)-yl)prop-2-en-1-one was prepared from4′-(4-phenoxyphenoxy)-1,2,5,6-tetrahydro-3,3′-bipyridine using Method E(24% yield). HPLC: 98%, RT=3.872 min. MS: m/z=399 [M+H]⁺, RT=1.97 min.

N-(3-((6-amino-5-(4-isopropoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A289)

N-(3-((6-amino-5-(4-isopropoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from6-(3-aminophenoxy)-5-(4-isopropoxyphenyl)pyrimidin-4-amine using MethodF (79% yield). HPLC: 100%, RT=3.826 min. MS: m/z=391 [M+H]⁺, RT=2.03min. ¹H-NMR (DMSO-d₆) δ 10.22 (s, 1H), 8.11 (s, 1H), 7.48 (s, 1H),7.36-7.26 (m, 4H), 6.76 (m, 3H), 6.39 (dd, 1H), 6.23 (d, 1H), 5.75 (d,1H), 4.63 (septet, 1H), 1.28 (d, 6H).

(E)-N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide(A290)

(E)-N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamidewas prepared from6-(4-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and(E)-4-(dimethylamino)but-2-enoic acid using Method E (29% yield). HPLC:99%, RT=3.448 min. MS: m/z=482 [M+H]⁺, RT=3.40 min. ¹H-NMR (DMSO-d₆) δ10.30 (s, 1H), 8.02 (s, 1H), 7.62 (d, 2H), 7.43-7.38 (m, 4H), 7.15 (tt,1H), 7.10-7.01 (m, 6H), 6.73 (m, 1H), 6.49 (broad s, 2H), 6.44 (d, 1H),3.93 (m, 2H), 2.80 (s, 6H).

N-(3-((6-amino-5-(5-methoxypyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A291)

N-(3-((6-amino-5-(5-methoxypyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from6-(3-aminophenoxy)-5-(5-methoxypyridin-3-yl)pyrimidin-4-amine usingMethod E (13% yield). HPLC: 99%, RT=2.429 min. MS: m/z=364 [M+H]⁺,RT=1.17 min. ¹H-NMR (DMSO-d₆) δ 10.15 (s, 1H), 8.32 (s, 1H), 8.26 (s,1H), 8.04 (s, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.39 (d, 1H), 7.23 (t,1H), 6.74 (m, 3H), 6.34 (dd, 1H), 6.18 (d, 1H), 5.69 (d, 1H), 3.83 (s,3H).

1-(4-(((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A292)

1-(4-(((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from5-(4-(benzyloxy)phenyl)-N4-(piperidin-4-ylmethyl)pyrimidine-4,6-diamineusing Method F (36% yield). HPLC: 100%, RT=3.678 min. MS: m/z=444[M+H]⁺, RT=1.65 min.

(E)-4-morpholino-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide(A293)

(E)-4-morpholino-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamidewas prepared from 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and(E)-4-morpholinobut-2-enoic acid using Method E (34% yield). HPLC: 100%,RT=3.493 min. MS: m/z=508 [M+H]⁺, RT=2.27 min.

N-(3-((6-amino-5-(4-(benzyloxy)-2,6-difluorophenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A294)

N-(3-((6-amino-5-(4-(benzyloxy)-2,6-difluorophenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from6-(3-aminophenoxy)-5-(4-(benzyloxy)-2,6-difluorophenyl)pyrimidin-4-amineusing Method F (14% yield). HPLC: 99%, RT=4.662 min. MS: m/z=475 [M+H]⁺,RT=2.40 min. ¹H-NMR (DMSO-D₆) δ 10.19 (s, 1H), 8.08 (s, 1H), 7.47-7.33(m, 7H), 7.28 (t, 1H), 6.92 (d, 2H), 6.81 (broad s, 2H), 6.70 (d, 1H),6.39 (dd, 1H), 6.23 (d, 1H), 5.74 (d, 1H), 5.14 (s, 2H).

(E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(4-(5-((4S)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)piperazin-1-yl)but-2-enamide(A295)

((E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(4-(5-((4S)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)piperazin-1-yl)but-2-enamidewas prepared from(E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(piperazin-1-yl)but-2-enamideand perfluorophenyl5-((4S)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoate usingMethod F (45% yield). HPLC: 100%, RT=3.635 min. MS: m/z=750 [M+H]⁺,RT=1.84 min.

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-ynamide (A296)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-ynamide was preparedfrom 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and but-2-ynoic acidusing Method E (63% yield). HPLC: 100%, RT=4.097 min. MS: m/z=421[M+H]⁺, RT=4.22 min. ¹H-NMR (DMSO-d₆) δ 10.75 (s, 1H), 8.71 (s, 1H),8.56 (d, 1H), 7.97 (s, 1H), 7.66 (d, 1H), 7.46 (t, 1H), 7.42-7.39 (m,3H), 7.28 (d, 2H), 7.17-7.13 (m, 3H), 7.05-7.02 (m, 3H), 2.04 (s, 3H).

N-(4-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide (A297)

N-(4-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide wasprepared from 4-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)aniline usingMethod E (41% yield). HPLC: 87%, RT=4.063 min. MS: m/z=409 [M+H]⁺,RT=4.05 min. ¹H-NMR (DMSO-d₆) δ 10.16 (s, 1H), 8.48 (s, 1H), 8.33 (d,1H), 7.68 (d, 2H), 7.60 (d, 2H), 7.35 (t, 2H), 7.12-7.08 (m, 3H),7.03-7.00 (m, 4H), 6.67 (d, 1H), 6.37 (dd, 1H), 6.20 (d, 1H), 5.70 (d,1H).

N-(1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-3-yl)acrylamide(A298)

N-(1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-3-yl)acrylamidewas prepared from6-(3-aminopiperidin-1-yl)-5-(4-phenoxyphenyl)pyrimidin-4-amine usingMethod F (14% yield). HPLC: 99%, RT=3.670 min. MS: m/z=416 [M+H]⁺,RT=1.55 min.

1-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one(A299)

1-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-onewas prepared from5-(4-phenoxyphenyl)-N4-(piperidin-4-yl)pyrimidine-4,6-diamine usingMethod F (52% yield). HPLC: 98%, RT=3.574 min. MS: m/z=416 [M+H]⁺,RT=1.74 min.

3-(3-aminophenyl)-4-(4-phenoxyphenoxy)pyridin-2-amine (A300)

3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline was prepared from3-iodo-4-(4-phenoxyphenoxy)pyridin-2-amine using Method C (37% yield).HPLC: 98%, RT=3.369 min. MS: m/z=370 [M+H]⁺, RT=3.37 min. ¹H-NMR(DMSO-d₆) δ 7.88 (d, 1H), 7.34 (t, 2H), 7.28 (s, 2H), 7.19 (t, 1H),7.13-7.08 (m, 3H), 7.03 (d, 2H), 6.97 (d, 2H), 6.73 (d, 1H), 6.67-6.65(m, 2H), 6.29 (d, 1H).

(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-(3,3-difluoropiperidin-1-yl)but-2-enamide(A301)

(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-(3,3-difluoropiperidin-1-yl)but-2-enamidewas prepared from5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine and(E)-4-(3,3-difluoropiperidin-1-yl)but-2-enoic acid using Method E (48%yield). HPLC: 97%, RT=3.809 min. MS: m/z=558 [M+H]⁺, RT=1.92 min.

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide (A302)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide was preparedfrom (3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine,triethylamine and tetrahydrofuran using Method G (6% yield). HPLC: 96%,RT=4.127 min. MS: m/z=423 [M+H]⁺, RT=3.22 min. ¹H-NMR (DMSO-d₆) δ 9.14(s, 1H), 9.02 (d, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 8.09 (d, 1H), 7.93(t, 1H), 7.87-7.84 (m, 3H), 7.73 (d, 2H), 7.62-7.58 (m, 3H), 7.51-7.50(m, 3H), 6.77 (dd, 1H), 6.67 (d, 1H), 6.03 (d, 1H), 5.02 (d, 2H).

6-(4-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine (A303)

6-(4-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine was preparedfrom 6-(4-aminophenoxy)-5-bromopyrimidin-4-amine using Method C (78%yield). HPLC: 98%, RT=3.259 min. MS: m/z=371 [M+H]⁺, RT=3.24 min. ¹H-NMR(DMSO-d₆) δ 8.05 (s, 1H), 7.43-7.38 (m, 5H), 7.21 (d, 2H), 7.17-7.06 (m,8H), 6.64 (broad s, 2H).

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2-ynamide (A304)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2-ynamide was preparedfrom (3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine andbut-2-ynoic acid using Method E (64% yield). HPLC: 98%, RT=4.069 min.MS: m/z=435 [M+H]⁺, RT=4.07 min. ¹H-NMR (DMSO-d₆) δ 9.01 (t, 1H), 8.51(s, 1H), 8.42 (d, 1H), 7.54-7.50 (m, 2H), 7.43-7.37 (m, 3H), 7.27 (d,1H), 7.22-7.18 (m, 2H), 7.13 (tt, 1H), 7.10-7.07 (m, 2H), 7.04-7.01 (m,2H), 6.79 (d, 1H), 4.33 (d, 2H), 1.93 (s, 3H).

6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine (A305)

6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine was preparedfrom 6-(3-aminophenoxy)-5-bromopyrimidin-4-amine using Method C (74%yield). HPLC: 99%, RT=3.417 min. MS: m/z=371 [M+H]⁺, RT=3.42 min. ¹H-NMR(DMSO-d₆) δ 8.09 (s, 1H), 7.42-7.38 (m, 4H), 7.20 (t, 1H), 7.15 (t, 1H),7.09-7.06 (m, 4H), 6.75 (d, 1H), 6.64-6.63 (m, 2H).

N-(3-(2-amino-4-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)acrylamide(A306)

N-(3-(2-amino-4-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)acrylamide wasprepared from 5-(3-aminophenyl)-4-(4-phenoxyphenoxy)pyrimidin-2-amineusing Method E (27% yield). HPLC: 96%, RT=4.208 min. MS: m/z=425 [M+H]⁺,RT=2.13 min. ¹H-NMR (DMSO-d₆) δ 10.22 (s, 1H), 8.27 (s, 1H), 7.93 (s,1H), 7.66 (d, 1H), 7.42-7.02 (m, 13H), 6.44 (dd, 1H), 6.25 (d, 1H), 5.75(d, 1H).

(E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide (A307)

(E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide wasprepared from 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and(E)-but-2-enoic acid using Method E (56% yield). HPLC: 98%, RT=4.292min. MS: m/z=423 [M+H]⁺, RT=4.28 min. ¹H-NMR (DMSO-d₆) δ 9.91 (s, 1H),8.52 (s, 1H), 8.43 (d, 1H), 7.92 (s, 1H), 7.68 (d, 1H), 7.40-7.37 (m,3H), 7.30 (d, 1H), 7.18-7.12 (m, 3H), 7.08 (d, 2H), 7.02 (d, 2H),6.83-6.76 (m, 2H), 6.14 (d, 1H), 1.86 (d, 3H).

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)propionamide(A308)

N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from6-(4-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and propionicacid using Method E (51% yield). HPLC: 96%, RT=4.165 min. MS: m/z=427[M+H]⁺, RT=4.11 min. ¹H-NMR (DMSO-d₆) δ 9.78 (s, 1H), 7.94 (s, 1H), 7.48(d, 2H), 7.36-7.32 (m, 4H), 7.09 (t, 1H), 7.02 (t, 4H), 6.91 (d, 2H),6.39 (broad s, 2H), 2.24 (q, 2H), 1.01 (t, 3H).

N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-3-yl)methyl)acrylamide(A309)

N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-3-yl)methyl)acrylamidewas prepared from6-(3-(aminomethyl)piperidin-1-yl)-5-(4-phenoxyphenyl)pyrimidin-4-amineusing Method F (43% yield). HPLC: 100%, RT=3.716 min. MS: m/z=430[M+H]⁺, RT=1.53 min.

N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide(A310)

N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide wasprepared from 3-iodo-4-(4-phenoxyphenoxy)pyridin-2-amine andN-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propionamideusing Method C (49% yield). HPLC: 98%, RT=4.186 min. MS: m/z=426 [M+H]⁺,RT=4.18 min. ¹H-NMR (DMSO-d₆) δ 10.01 (s, 1H), 7.94 (d, 1H), 7.73 (s,1H), 7.63 (d, 1H), 7.44 (t, 1H), 7.39 (t, 2H), 7.24 (s, 2H), 7.16-7.01(m, 8H), 6.35 (d, 1H), 2.32 (q, 2H), 1.07 (t, 3H).

(R)—N-(3-(4-amino-6-((1-phenylethyl)amino)pyrimidin-5-yl)phenyl)acrylamide(A311)

(R)—N-(3-(4-amino-6-((1-phenylethyl)amino)pyrimidin-5-yl)phenyl)acrylamidewas prepared from(R)-5-(3-aminophenyl)-N4-(1-phenylethyl)pyrimidine-4,6-diamine usingMethod F (16% yield). HPLC: 100%, RT=3.515 min. MS: m/z=360 [M+H]⁺,RT=1.73 min. ¹H-NMR (DMSO-d₆), δ 10.33 (s, 1H), 8.28 (s, 1H), 7.82 (s,1H), 7.64 (d, 1H), 7.52 (t, 1H), 7.29-6.85 (m, 9H), 6.47 (dd, 1H), 6.27(d, 1H), 5.77 (d, 1H), 5.40 (s, 1H), 1.39 (d, 3H).

3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline (A312)

3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline was prepared from3-bromo-4-(4-phenoxyphenoxy)pyridine using Method C (55% yield). HPLC:100%, RT=3.396 min. MS: m/z=355 [M+H]⁺, RT=2.88 min.

4-(3-aminophenoxy)-3-(4-phenoxyphenyl)pyridin-2-amine (A313)

4-(3-aminophenoxy)-3-(4-phenoxyphenyl)pyridin-2-amine was prepared from4-(3-aminophenoxy)-3-iodopyridin-2-amine using Method C (84% yield).HPLC: 98%, RT=3.490 min. MS: m/z=370 [M+H]⁺, RT=3.44 min. ¹H-NMR(DMSO-d₆) δ 8.00 (d, 1H), 7.45-7.41 (m, 6H), 7.18 (t, 1H), 7.13-7.07 (m,5H), 6.51 (d, 1H), 6.32-6.26 (m, 3H).

4-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline (A314)

4-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline was prepared from3-bromo-4-(4-phenoxyphenoxy)pyridine using Method C (74% yield). HPLC:100%, RT=3.456 min. MS: m/z=355 [M+H]⁺, RT=2.75 min.

(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine (A315)

(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine was preparedfrom 3-bromo-4-(4-phenoxyphenoxy)pyridine using Method C (62% yield).HPLC: 95%, RT=3.286 min. MS: m/z=369 [M+H]⁺, RT=2.19 min.

(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine (A316)

(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine was preparedfrom 3-bromo-4-(4-phenoxyphenoxy)pyridine using Method C (71% yield).HPLC: 95%, RT=3.376 min. MS: m/z=369 [M+H]⁺, RT=2.29 min.

5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine (A317)

5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine was preparedfrom 5-bromo-6-(4-phenoxyphenoxy)pyrimidin-4-amine using Method C (76%yield). HPLC: 97%, RT=3.433 min. MS: m/z=371 [M+H]⁺, RT=3.48 min. ¹H-NMR(DMSO-d₆) δ 8.01 (s, 1H), 7.34-7.26 (m, 3H), 7.06 (t, 1H), 7.01-6.87 (m,9H), 6.41 (broad s, 2H).

N-(3-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)propionamide (A318)

N-(3-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)propionamide wasprepared from 3-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)aniline usingMethod E (100% yield). HPLC: 96%, RT=4.161 min. MS: m/z=409 [M+H]⁺,RT=4.15 min. ¹H-NMR (DMSO-d₆) δ 10.37 (s, 1H), 8.78 (s, 1H), 8.55 (d,1H), 7.72-7.70 (m, 3H), 7.45-7.40 (m, 4H), 7.18 (t, 1H), 7.13-7.07 (m,4H), 7.03 (d, 1H), 6.97 (s, 1H), 6.41 (dd, 1H), 6.24 (d, 1H), 5.77 (d,1H).

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide (A319)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide was preparedfrom 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and pyridine instead ofN, N-diethylethanamine, 1-methylpyrrolidin-2-one, dichloromethane usingMethod G (65% yield). HPLC: 92%, RT=4.234 min. MS: m/z=411 [M+H]⁺,RT=3.35 min.

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide (A320)

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide was preparedfrom 4-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline and pyridine instead ofN, N-diethylethanamine, 1-methylpyrrolidin-2-one, dichloromethane usingMethod G (77% yield). HPLC: 98%, RT=4.157 min. MS: m/z=411 [M+H]⁺,RT=3.39 min.

N-(4-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)propionamide (A321)

N-(4-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)propionamide wasprepared from 4-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)aniline usingMethod E (98% yield). HPLC: 96%, RT=4.061 min. MS: m/z=411 [M+H]⁺,RT=4.01 min. ¹H-NMR (DMSO-d₆) δ 9.93 (s, 1H), 8.53 (s, 1H), 8.37 (d,1H), 7.67-7.65 (m, 4H), 7.41 (t, 2H), 7.16 (t, 1H), 7.12-7.06 (m, 6H),6.69 (d, 1H), 2.31 (q, 2H), 1.08 (t, 3H).

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methacrylamide (A322)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methacrylamide wasprepared from 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline andmethacrylic acid using Method E (56% yield). HPLC: 98%, RT=4.345 min.MS: m/z=423 [M+H]⁺, RT=4.33 min. ¹H-NMR (DMSO-d₆), 1H), 8.51 (s, 1H),8.42 (d, 1H), 7.96 (s, 1H), 7.73 (d, 1H), 7.42-7.33 (m, 4H), 7.19 (d,2H), 7.13 (t, 1H), 7.09 (d, 2H), 7.02 (d, 2H), 6.79 (d, 1H), 5.80 (s,1H), 5.51 (s, 1H), 1.94 (s, 3H).

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide (A323)

N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide was preparedfrom (3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine andpyridine instead of N, N-diethylethanamine, 1-methylpyrrolidin-2-one,dichloromethane using Method G (58% yield). HPLC: 97%, RT=4.034 min. MS:m/z=425 [M+H]⁺, RT=3.34 min.

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide (A324)

N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide was preparedfrom (4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine andpyridine instead of N, N-diethylethanamine, 1-methylpyrrolidin-2-one,dichloromethane using Method G (43% yield). HPLC: 99%, RT=4.032 min. MS:m/z=425 [M+H]⁺, RT=3.22 min.

N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)propionamide(A325)

N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)propionamide wasprepared from 5-bromo-6-(4-phenoxyphenoxy)pyrimidin-4-amine andN-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propionamideusing Method C (82% yield). HPLC: 99%, RT=4.286 min. MS: m/z=427 [M+H]⁺,RT=4.25 min. ¹H-NMR (DMSO-d₆) δ 9.93 (s, 1H), 8.10 (s, 1H), 7.64-7.63(m, 2H), 7.38 (t, 3H), 7.12 (t, 1H), 7.08-7.05 (m, 3H), 6.99 (d, 4H),6.60 (broad s, 2H), 2.32 (q, 2H), 1.07 (t, 3H).

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)propionamide(A326)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)propionamidewas prepared from6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine using Method E(61% yield). HPLC: 94%, RT=4.262 min. MS: m/z=427 [M+H]⁺, RT=4.22 min.¹H-NMR (DMSO-d₆) δ 9.90 (s, 1H), 8.03 (s, 1H), 7.41-7.38 (m, 5H), 7.29(d, 1H), 7.23 (t, 1H), 7.15 (t, 1H), 7.07 (t, 4H), 6.70 (d, 1H), 6.49(broad s, 2H), 2.28 (q, 2H), 1.04 (t, 3H).

(E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2-enamide (A327)

(E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2-enamide wasprepared from (3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamineand (E)-but-2-enoic acid using Method E (72% yield). HPLC: 95%, RT=4.079min. MS: m/z=437 [M+H]⁺, RT=4.07 min. ¹H-NMR (DMSO-d₆) δ 8.51 (s, 1H),8.42-8.39 (m, 2H), 7.53-7.52 (m, 2H), 7.43-7.37 (m, 3H), 7.28 (d, 1H),7.19 (d, 2H), 7.14 (t, 1H), 7.08 (d, 2H), 7.02 (d, 2H), 6.78 (d, 1H),6.63 (qd, 1H), 5.94 (d, 1H), 4.38 (d, 2H), 1.76 (d, 3H).

3-(4-phenoxyphenyl)-4-(3-propionamidophenoxy)picolinamide (A328)

3-(4-phenoxyphenyl)-4-(3-propionamidophenoxy)picolinamide was preparedfrom 4-(3-aminophenoxy)-3-(4-phenoxyphenyl)picolinamide using Method F(24% yield). HPLC: 100%, RT=4.113 min. MS: m/z=452 [M+H]⁺, RT=2.05 min.¹H-NMR (DMSO-d₆) δ 10.23 (s, 1H), 8.37 (d, 1H), 7.78 (s, 1H), 7.48 (s,1H), 7.36-7.29 (m, 7H), 7.09 (t, 1H), 6.97 (d, 2H), 6.92 (d, 2H), 6.84(d, 1H), 6.74 (d, 1H), 6.33 (dd, 1H), 6.18 (d, 1H), 5.70 (d, 1H).

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-1-cyanocyclopropanecarboxamide(A329)

N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-1-cyanocyclopropanecarboxamidewas prepared from6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and1-cyanocyclopropanecarboxylic acid using Method E (42% yield). HPLC:96%, RT=4.467 min. MS: m/z=464 [M+H]⁺, RT=2.24 min. ¹H-NMR (DMSO-d₆) δ10.85 (s, 1H), 8.91 (s, 1H), 8.22-8.08 (m, 7H), 7.96 (t, 1H), 7.90-7.87(m, 4H), 7.63 (d, 1H), 7.54 (broad s, 2H), 3.30 (s, 4H).

N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-1-cyanocyclopropanecarboxamide(A330)

N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-1-cyanocyclopropanecarboxamidewas prepared from5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine and1-cyanocyclopropanecarboxylic acid using Method E (66% yield). HPLC:100%, RT=4.485 min. MS: m/z=465 [M+H]⁺, RT=2.26 min. ¹H-NMR (DMSO-d₆) δ10.07 (s, 1H), 8.10 (s, 1H), 7.64-7.61 (m, 2H), 7.43-7.36 (m, 3H), 7.18(d, 1H), 7.11 (t, 1H), 7.06 (d, 2H), 7.00-6.97 (m, 4H), 6.58 (broad s,2H), 1.65 (s, 4H).

(E)-3-(7-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)naphthalen-2-yl)-N,N-dimethylacrylamide(A331)

(E)-3-(7-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)naphthalen-2-yl)-N,N-dimethylacrylamidewas prepared from(E)-3-(7-((6-amino-5-chloropyrimidin-4-yl)oxy)naphthalen-2-yl)-N,N-dimethylacrylamideusing Method C (16% yield). HPLC: 93%, RT=4.680 min. MS: m/z=503 [M+H]⁺,RT=2.54 min. ¹H-NMR (DMSO-d₆) δ 8.09 (d, 2H), 7.94 (d, 2H), 7.66-7.58(m, 2H), 7.50 (d, 2H), 7.42 (t, 2H), 7.36-7.31 (m, 2H), 7.18 (t, 1H),7.12-7.10 (m, 5H), 6.70 (broad s, 2H), 3.21 (s, 3H), 2.96 (s, 3H).

1-(4-(1-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)piperidin-1-yl)prop-2-en-1-one(A332)

1-(4-(1-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)piperidin-1-yl)prop-2-en-1-onewas prepared from5-(4-phenoxyphenyl)-N4-(1-(piperidin-4-yl)ethyl)pyrimidine-4,6-diamineusing Method F (30% yield). HPLC: 100%, RT=4.388 min. MS: m/z=444[M+H]⁺, RT=1.66 min. ¹H-NMR (DMSO-d₆) (s, 1H), 7.38 (t, 2H), 7.19-7.06(m, 7H), 6.85 (broad s, 2H), 6.70 (m, 1H), 6.52 (d, 1H), 5.99 (d, 1H),5.56 (t, 1H), 4.33 (t, 1H), 3.96 (t, 2H), 2.86 (m, 1H), 1.62-1.54 (m,3H), 1.00 (d, 3H), 0.95-0.84 (m, 2H).

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)propan-1-one(A333)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)propan-1-onewas prepared from5-(4-phenoxyphenyl)-N4-(piperidin-4-ylmethyl)pyrimidine-4,6-diamineusing Method E (43% yield). HPLC: 99%, RT: 4.412 min. MS: m/z=432[M+H]⁺, RT=1.49 min. ¹H-NMR (DMSO-d₆) (s, 1H), 7.38 (t, 2H), 7.20 (d,2H), 7.15-6.94 (m, 8H), 4.27 (d, 1H), 3.74 (d, 1H), 3.16 (s, 2H), 2.83(t, 1H), 2.39 (t, 1H), 2.21 (q, 2H), 1.72 (m, 1H), 1.51 (t, 2H),0.96-0.79 (m, 5H).

1-(4-(((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A334)

1-(4-(((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from5-(4-phenoxyphenyl)-N-(piperidin-4-ylmethyl)pyrimidin-4-amine usingMethod F (6% yield). HPLC: 99%, RT=4.533 min. MS: m/z=415 [M+H]⁺,RT=1.67 min.

1-(4-(((6-amino-5-(4-(pyridin-2-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one(A335)

1-(4-(((6-amino-5-(4-(pyridin-2-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared fromN4-(piperidin-4-ylmethyl)-5-(4-(pyridin-2-yloxy)phenyl)pyrimidine-4,6-diamineusing Method F (28% yield). HPLC: 100%, RT: 4.401 min. MS: m/z=431[M+H]⁺, RT=1.32 min. ¹H-NMR (DMSO-d₆) □ (s, 1H), 8.18 (d, 1H), 7.84 (t,1H), 7.23 (s, 4H), 7.14 (t, 1H), 7.03-7.01 (m, 2H), 6.82 (broad s, 2H),6.71 (dd, 1H), 5.99 (d, 1H), 5.57 (d, 1H), 4.30 (d, 1H), 3.95 (d, 1H),3.17 (m, 2H), 2.91 (t, 1H), 2.51 (t, 1H), 1.76 (m, 1H), 1.54 (m, 2H),0.90 (m, 2H).

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2-yn-1-one(A336)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2-yn-1-onewas prepared from5-(4-phenoxyphenyl)-N4-(piperidin-4-ylmethyl)pyrimidine-4,6-diamineusing Method E (48% yield). HPLC: 99%, RT: 4.553 min. MS: m/z=442[M+H]⁺, RT=1.62 min. ¹H-NMR (DMSO-d₆) □ (s, 1H), 7.38 (t, 2H), 7.20 (d,2H), 7.13 (t, 1H), 7.10-7.05 (dd, 4H), 7.00 (m, 1H), 6.85 (broad s, 2H),4.15 (t, 2H), 3.16 (m, 2H) m 2.97 (t, 1H), 2.53 (t, 1H), 1.93 (s, 3H),1.75 (m, 1H), 1.60-1.51 (dd, 2H), 0.98-0.80 (m, 2H).

N4-((1-(6-chloropyridin-2-yl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine(A337)

N4-((1-(6-chloropyridin-2-yl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diaminewas prepared from5-(4-phenoxyphenyl)-N4-(piperidin-4-ylmethyl)pyrimidine-4,6-diamine and2,6-dichloropyridine using Method B (25% yield). HPLC: 99%, RT: 5.214min. MS: m/z=487 [M+H]⁺, RT=2.11 min. ¹H-NMR (DMSO-d₆) □ (s, 1H),7.44-7.36 (m, 3H), 7.20 (d, 2H), 7.15-6.95 (m, 8H), 6.69 (d, 1H), 6.52(d, 1H), 4.14 (d, 2H), 3.18 (m, 2H), 2.71 (t, 2H), 1.77 (m, 1H), 1.56(d, 2H), 0.98 (m, 2H).

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-one(A338)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-onewas prepared from5-(4-phenoxyphenyl)-6-(piperidin-4-ylmethoxy)pyrimidin-4-amine usingMethod F (10% yield). HPLC: 100%, RT: 4.366 min. MS: m/z=431 [M+H]⁺,RT=2.04 min. ¹H-NMR (DMSO-d₆) (s, 1H), 7.35 (t, 2H), 7.21 (d, 2H), 7.10(t, 1H), 7.02-6.97 (dd, 4H), 6.69 (dd, 1H), 6.40 (broad s, 2H), 6.98 (d,1H), 5.55 (d, 1H), 4.30 (d, 1H), 4.04 (d, 2H), 3.93 (d, 1H), 2.92 (t,1H), 2.51 (t, 1H), 1.83 (m, 1H), 1.53 (m, 2H), 0.97 (m, 2H). min.

N-(3-((6-amino-5-(4-(benzyloxy)-2,5-difluorophenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide(A339)

N-(3-((6-amino-5-(4-(benzyloxy)-2,5-difluorophenyl)pyrimidin-4-yl)oxy)phenyl)acrylamidewas prepared from6-(3-aminophenoxy)-5-(4-(benzyloxy)-2,5-difluorophenyl)pyrimidin-4-amineusing Method F (69% yield). HPLC: 89%, RT: 5.442 min. MS: m/z=475[M+H]⁺, RT=2.38 min. ¹H-NMR (DMSO-d₆) □ (s, 1H), 8.00 (s, 1H), 7.42-7.20(m, 11H), 6.67 (m, 3H), 6.34 (dd, 1H), 6.18 (d, 1H), 5.69 (d, 1H), 5.15(d, 2H).

N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)but-2-ynamide(A340)

N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)but-2-ynamidewas prepared from 4-(3-aminophenoxy)-3-(4-phenoxyphenyl)pyridin-2-amineusing Method E (13% yield). HPLC: 98%, RT: 4.676 min. MS: m/z=436[M+H]⁺, RT=1.95 min. ¹H-NMR (DMSO-d₆) □ (s, 1H), 7.92 (d, 1H), 7.48 (s,1H), 7.43-7.34 (m, 6H), 7.28 (broad s, 2H), 7.17 (t, 1H), 7.09 (t, 4H),6.86 (d, 1H), 6.30 (d, 1H), 2.03 (s, 3H).

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)but-2-yn-1-one(A341)

(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)but-2-yn-1-onewas prepared from(R)-5-(4-phenoxyphenyl)-N4-(pyrrolidin-3-yl)pyrimidine-4,6-diamine usingMethod E (32% yield). HPLC: 99%, RT: 4.106 min. MS: m/z=414 [M+H]⁺,RT=1.56 min.

N-{3-[6-Amino-5-(4-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloroacetamide(A342)

N-{3-[6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloroacetamideWas prepared using Method E (41.5% yield). HPLC: 97%, RT: 4.26 min. MS:m/z=447 [M+H]⁺, RT=4.24 min. 1H-NMR: 400 MHz, DMSO-d₆: δ 10.45 (s, 1H),8.05 (s, 1H), 7.40-7.36 (m, 5H), 7.36-7.26 (m, 2H), 7.17-7.12 (m, 1H),7.09-7.05 (m, 4H), 6.79-6.76 (m, 1H), 6.50 (brs, 2H), 4.23 (s, 2H).

N-(3-{6-Amino-5-[4-(2-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-acrylamide(A343)

N-(3-{6-Amino-5-[4-(2-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-acrylamidewas prepared using Method E (56.5% yield) HPLC: 94%, RT: 4.22 min. MS:m/z=457 [M+H]⁺, RT=4.22 min. 1H-NMR: 400 MHz, DMSO-d₆: δ 8.19 (s, 1H),7.71 (s, 1H), 7.52 (t, J=8.00 Hz, 1H), 7.41-7.33 (m, 6H), 7.21-7.10 (m,6H), 6.84 (d, J=8.00 Hz, 1H), 6.44 (d, J=16.00 Hz, 1H), 6.22 (dd,J=18.00, 12.00 Hz, 1H), 5.81 (d, J=12.00 Hz, 1H), 5.19 (s, 2H).

N-(3-{6-Amino-5-[4-(4-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-acrylamide(A344)

N-(3-{6-Amino-5-[4-(4-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-acrylamidewas produced according to Method E (5.1% yield) HPLC: 92%, RT: 4.22 min.MS: m/z=457 [M+H]⁺, RT=4.22 min. ¹H-NMR: 400 MHz, DMSO-d₆: δ 10.20 (s,1H), 8.06 (s, 1H), 7.53-7.49 (m, 2H), 7.46-7.45 (m, 1H), 7.37-7.20 (m,6H), 7.10 (d, J=8.00 Hz, 2H), 6.76-6.74 (m, 1H), 6.60 (brs, 2H), 6.39(dd, J=18.00, 12.00 Hz, 1H), 6.25-6.21 (m, 1H), 5.75 (d, J=8.00 Hz, 1H),5.15 (s, 2H).

N-(3-{6-Amino-5-[4-(3-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-2-chloro-acetamide(A345)

N-(3-{6-Amino-5-[4-(3-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-2-chloro-acetamidewas produced according to Method E (14.3% Yield). HPLC: 98%, RT: 4.35min. MS: m/z=479 [M+H]⁺, RT=4.41 min. ¹H-NMR: 400 MHz, DMSO-d₆: δ 10.35(s, 1H), 8.02 (s, 1H), 7.47-7.42 (m, 1H), 7.35-7.26 (m, 7H), 7.18-7.16(m, 1H), 7.10 (d, J=8.00 Hz, 2H), 6.78-6.75 (m, 1H), 6.43 (brs, 2H),5.15 (s, 2H), 4.23 (s, 2H).

N-{3-[6-Amino-5-(4-benzyloxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-propionamide(A346)

N-{3-[6-Amino-5-(4-benzyloxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-propionamidewas produced according to Method E (6.8% Yield). HPLC: 91%, RT: 4.18min. MS: m/z=441 [M+H]⁺, RT=4.23 min. ¹H-NMR: 400 MHz, DMSO-d₆: δ 9.90(s, 1H), 8.01 (s, 1H), 7.46 (d, J=8.00 Hz, 2H), 7.41-7.27 (m, 7H), 7.22(t, J=8.00 Hz, 1H), 7.10 (d, J=8.00 Hz, 2H), 6.70-6.67 (m, 1H), 6.45(brs, 2H), 5.11 (s, 2H), 2.28 (q, J=8.00 Hz, 2H), 1.05 (t, J=4.00 Hz,3H).

N-{3-[6-Amino-5-(4-benzyloxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloro-acetamide(A347)

N-{3-[6-Amino-5-(4-benzyloxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloro-acetamidewas produced according to Method E (27.6% yield) HPLC: 95%, RT: 4.31min. MS: m/z=461 [M+H]⁺, RT=4.29 min. ¹H-NMR: 400 MHz, DMSO-d₆: δ 10.35(s, 1H), 8.02 (s, 1H), 7.46 (d, J=8.00 Hz, 2H), 7.39 (t, J=4.00 Hz, 2H),7.35-7.26 (m, 6H), 7.10 (d, J=8.00 Hz, 2H), 6.78-6.75 (m, 1H), 6.48(brs, 2H), 5.11 (s, 2H), 4.22 (s, 2H).

N-{3-[6-Amino-5-(4-benzyloxy-3-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-acrylamide(A348)

N-{3-[6-Amino-5-(4-benzyloxy-3-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-acrylamidewas produced according to Method E (23.2% Yield) HPLC: 98%, RT: 4.30min. MS: m/z=457 [M+H]⁺, RT=4.35 min. ¹H-NMR: 400 MHz, DMSO-d₆: δ 10.20(s, 1H), 8.03 (s, 1H), 7.48-7.45 (m, 3H), 7.41 (t, J=8.00 Hz, 2H),7.38-7.25 (m, 5H), 7.15 (d, J=8.00 Hz, 1H), 6.77-6.75 (m, 1H), 6.56(brs, 2H), 6.40 (dd, J=16.00, 12.00 Hz, 1H), 6.26-6.21 (m, 1H), 5.75 (d,J=8.00 Hz, 1H), 5.19 (s, 2H).

N-{3-[6-Amino-5-(4-benzyloxy-2-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-acrylamide(A349)

N-{3-[6-Amino-5-(4-benzyloxy-2-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-acrylamidewas produced according to Method E (11.8% yield). HPLC: 97%, RT: 4.35min. MS: m/z=457 [M+H]⁺, RT=4.39 min. ¹H-NMR: 400 MHz, DMSO-d₆: δ 10.20(s, 1H), 8.05 (s, 1H), 7.47-7.25 (m, 9H), 7.02 (d, J=12.00 Hz, 1H), 6.95(d, J=8.00 Hz, 1H), 6.73-6.70 (m, 1H), 6.60 (brs, 2H), 6.38-6.36 (m,1H), 6.26-6.21 (m, 1H), 5.75 (d, J=8.00 Hz, 1H), 5.13 (s, 2H).

N-{3-(6-Amino-5-(4-benzyloxy-2-fluoro-phenyl)-pyrimidin-4-yloxy}-phenyl)-2-chloro-acetamide(A350)

N-{3-(6-Amino-5-(4-benzyloxy-2-fluoro-phenyl)-pyrimidin-4-yloxy}-phenyl)-2-chloro-acetamidewas produced according to Method E. HPLC: 95%, RT: 4.52 min. MS: m/z=479[M+H]⁺, RT=4.41 min. ¹H-NMR: 400 MHz, DMSO-d₆: δ 10.37 (s, 1H), 8.06 (s,1H), 7.48-7.27 (m, 9H), 7.03 (d, J=12.00 Hz, 1H), 6.95 (d, J=8.00 Hz,1H), 6.75 (d, J=4.00 Hz, 1H), 6.59 (brs, 2H), 5.14 (s, 2H), 4.23 (s,2H).

N-{3-[6-Amino-5-(4-benzyloxy-3-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloro-acetamide(A351)

N-{3-[6-Amino-5-(4-benzyloxy-3-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloro-acetamidewas produced according to Method (27.6% yield). HPLC: 98%, RT: 4.39 min.MS: m/z=479 [M+H]⁺, RT=4.37 min. ¹H-NMR: 400 MHz, DMSO-d₆: δ 10.35 (s,1H), 8.02 (s, 1H), 7.48-7.47 (m, 2H), 7.41 (t, J=8.00 Hz, 2H), 7.36-7.25(m, 6H), 7.15 (d, J=8.00 Hz, 1H), 6.80-6.77 (m, 1H), 6.51 (brs, 2H),5.19 (s, 2H), 4.23 (s, 2H).

N-{4-[4-(3-Acryloylamino-phenoxy)-6-amino-pyrimidin-5-yl]-phenyl}-benzamide(A352)

N-{4-[4-(3-Acryloylamino-phenoxy)-6-amino-pyrimidin-5-yl]-phenyl}-benzamidewas produced according to Method E (8.8% yield). HPLC: 92%, RT: 3.48min. MS: m/z=452 [M+H]⁺, RT=3.53 min. ¹H-NMR: 400 MHz, DMSO-d₆: δ 10.36(s, 1H), 10.20 (s, 1H), 8.04 (s, 1H), 7.95 (d, J=8.00 Hz, 2H), 7.89 (d,J=8.00 Hz, 2H), 7.60-7.52 (m, 3H), 7.46 (s, 1H), 7.39-7.37 (m, 3H), 7.28(t, J=8.00 Hz, 1H), 6.77 (d, J=8.00 Hz, 1H), 6.50 (brs, 2H), 6.40 (dd,J=16.00, 12.00 Hz, 1H), 6.24 (d, J=16.00 Hz, 1H), 6.75 (d, J=8.00 Hz,1H).

Biological Activity

Description of In Vitro Assays

BTK IC50 Enzyme Assay

The following describes a microfluidic, off-chip mobility shift kinaseassay used to measure inherent potency of compounds against BTK enzyme.Compounds described by embodiments of the present invention were assayedusing this protocol and the data from the same is recorded in Table 2within the column labeled: “Time Dependent BTK Enzyme Assay IC₅₀”. TheseIC₅₀ values are reported in ranges wherein: A<100 nM, B<1 uM, and C>1uM.

2.5× stocks of full-length human BTK (08-080) from CarnaBio USA, Inc.,Natick, Mass., 1.6×ATP and appropriate kinKDR peptide substrate(FITC-AHA-EEPLYWSFPAKKK-NH2) were prepared in kinase reaction bufferconsisting of 25 mM MgCl2, 0.015% Brij-35 (30%), 100 mM Hepes, pH 7.5,and 10 mM DTT.

5 uL of enzyme buffer and 7.5 uL of ATP/kinKDR peptide substrate mixwere added to Matrix (#115304) 384-well, sterile, polypropylene plates(Thermo Fisher Scientific, Hudson, N.H.) with 125 nL of serially dilutedcompounds prepared in 100% DMSO, and incubated for 90 min. at 27 C.Following the incubation period, reactions were stopped by adding 60 uLstop buffer consisting of 100 mM Hepes, pH 7.5, 0.015% Brij-35 (30%),0.277% Coating Reagent #3 (Caliper Life Sciences, Mountain View,Calif.), 5% DMSO. Stopped reactions were monitored at −2 PSI, −3000V/−700 V in a LabChip 3000 plate reader from Caliper Life Sciences, aPerkinElmer Company (Hopkinton, Mass.), and the activity was measured byoff-chip mobility shift assay measuring the charge/mass differencebetween substrate and product resulting from peptide phosphorilation.IC50 and efficacy were determined by plotting log [Inhibitor] vs. %Activity in GeneData Screener (Basel, Switzerland). Compounds describedby embodiments of the present invention were assayed using this protocoland the data from the same is recorded in Table 2 within the columnlabeled: “Time Dependent PBMC BTK Enzyme Assay IC50.” These IC₅₀ valuesare reported in ranges wherein: A<100 nM, B<1 uM, and C>1 uM. I<1 uM andII>1 uM.

Time Dependent Human Whole Blood IC50 Assay

Compounds described by embodiments of the present invention were assayedusing a human whole blood assay. The data from the same is recorded inTable 2 within the column labeled: “Time Dependent Human Whole Blood BTKEnzyme Assay IC₅₀”. These IC₅₀ values are reported in ranges wherein:I<1 uM and II>1 uM.

Time Dependent PMBC IC50 Assay

Compounds described by embodiments of the present invention were assayedusing a time dependent PMBC assay. The data from the same is recorded inTable 2 within the column labeled: “Time Dependent PBMC Assay IC50.”These IC₅₀ values are reported in ranges wherein: I<1 uM and II>1 uM.

Table 2 presents IC₅₀ values, derived from the in vitro assays detailedabove, for selected compounds described by embodiments of the presentinvention.

TABLE 2 Time Dependent Human Whole Time Dependent Blood Time DependentBTK Enzyme BTK Enzyme PBMC Compound Assay Assay Assay No. IC₅₀ IC₅₀ IC₅₀“A1” A I I “A2” — — — “A3” A I I “A4” A I I “A5” — — — “A6” A — I “A7” C— — “A8” — — — “A9” A — — “A10” A — I “A11” C — — “A12” — — — “A13” C —— “A14” — — — “A15” — — — “A16” C — — “A17” A — — “A18” B — — “A19” A —— “A20” C — — “A21” A — — “A22” — — — “A23” — — — “A24” C — — “A25” C —— “A26” A — I “A27” C — — “A28” A — — “A29” — — — “A30” — — — “A31” — —— “A32” — — — “A33” C — — “A34” A — I “A35” C — — “A36” C — — “A37” A II “A38” A — I “A39” B — — “A40” B — — “A41” A — — “A42” B — — “A43” B —— “A44” C — — “A45” A — I “A46” A — — “A47” B — — “A48” A II I “A49” BII I “A50” B — — “A51” A — I “A52” A — I “A53” B — — “A54” — — — “A55” —— — “A56” C — — “A57” — — — “A58” A — — “A59” B — — “A60” A — — “A61” A— — “A62” B — — “A63” B — — “A64” A — I “A65” A — — “A66” A — — “A67” A— I “A68” A — — “A69” B — — “A70” A — I “A71” B — — “A72” A — — “A73” B— — “A74” B — — “A75” A — I “A76” B — — “A77” C — — “A78” C — — “A79” B— — “A80” B — — “A81” C — — “A82” C — — “A83” B — — “A84” C — — “A85” C— — “A86” B — — “A87” B — — “A88” A — — “A89” — — — “A90” — — — “A91” —— — “A92” B — — “A93” B — — “A94” C — — “A95” A — — “A96” B — — “A97” B— — “A98” A — — “A99” B — — “A100 — — — “A101” — — — “A102” C — — “A103”B — — “A104” A — — “A105” A — I “A106” A — II “A107” B — — “A108” A — —“A109” A — — “A110” A — — “A111” A — — “A112” A — — “A113” A — I “A114”A — II “A115” A — II “A116” C — — “A117” A — I “A118” A — I “A119” A — —“A120” A I I “A121” A — I “A122” C — — “A123” C — — “A124” A — I “A125”C — — “A126” A — I “A127” A — I “A128” — — — “A129” — — — “A130” — — —“A131” — — — “A132” — — — “A133” — — — “A134” — — — “A135” — — — “A136”— — — “A137” — — — “A138” — — — “A139” — — — “A140” — — — “A141” B — —“A142” A — — “A143” A — — “A144” A — — “A145” A — — “A146” A — — “A147”A — — “A148” B — — “A149” B — — “A150” B — — “A151” A — II “A152” B — —“A153” B — — “A154” C — — “A155” C — — “A156” B — — “A157” C — — “A158”A — — “A159” C — — “A160” B — — “A161” A — — “A162” A — — “A163” C — —“A164” C — — “A165” A — — “A166” B — — “A167” A — — “A168” C — II “A169”A — — “A170” A — — “A171” — — — “A172” A I I “A173” A — — “A174” C — —“A175” B — — “A176” C — — “A177” A — — “A178” A — — “A179” B — — “A180”B — — “A181” A — — “A182” A — — “A183” A — — “A184” A — — “A185” A — —“A186” A — — “A187” A — — “A188” B — — “A189” A — — “A190” A — — “A191”A — — “A192” B — — “A193” C — — “A194” A — — “A195” A — — “A196” B — —“A197” B — — “A198” A — — “A199” B — — “A200” B — — “A201” B — — “A202”A — — “A203” A — — “A204” A — — “A205” A — — “A206” A — — “A207” B — —“A208” C — — “A209” B — — “A210” B — — “A211” B — — “A212” A — — “A213”— — — “A214” — — — “A215” A — — “A216” A — — “A217” B — — “A218” B — —“A219” C — — “A220” B — — “A221” C — — “A222” A — — “A223” B — — “A224”A — — “A225” A — — “A226” B — — “A227” A — — “A228” B — — “A229” — — —“A230” — — — “A231” — — — “A232” — — — “A233” — — — “A234” — — — “A235”C — — “A236” — — — “A237” — — — “A238” — — — “A239” — — — “A240” A — —“A241” A — — “A242” A — I “A243” A — — “A244” A — — “A245” A — I “A246”A I I “A247” A — I “A248” A — — “A249” A — — “A250” A I I “A251” A I I“A252” A — I “A253” A — I “A254” A — — “A255” A — I “A256” A — — “A257”A — — “A258” A — II “A259” A — — “A260” A — — “A261” A — — “A262” A — I“A263” B — — “A264” A — — “A265” A — — “A266” A — I “A267” A — — “A268”A — — “A269” A — — “A270” A — — “A271” A — — “A272” A — — “A273” A — —“A274” A — — “A275” A — — “A276” A — — “A277” A — — “A278” A — — “A279”A — — “A280” A — — “A281” B — — “A282” A — — “A283” B — — “A284” B — —“A285” B — — “A286” B — — “A287” B — — “A288” B — — “A289” B — — “A290”B — — “A291” B — — “A292” B — — “A293” — — — “A294” B — — “A295” — — —“A296” B — — “A297” C — — “A298” C — — “A299” C — — “A300” B — — “A301”C — — “A302” C — — “A303” C — — “A304” C — — “A305” C — — “A306” A — I“A307” C — — “A308” C — — “A309” C — — “A310” C — — “A311” C — — “A312”C — — “A313” C — — “A314” C — — “A315” C — — “A316” C — — “A317” C — —“A318” C — — “A319” C — — “A320” — — — “A321” — — — “A322” C — — “A323”— — — “A324” C — — “A325” C — — “A326” C — — “A327” C — — “A328” C — —“A329” C — — “A330” C — — “A331” — — — “A332” — — — “A333” B — — “A334”A — — “A335” B — — “A336” A — I “A337” C — — “A338” B — — “A339” A — —“A340” A — — “A341” A — I “A342” A — — “A343” — — — “A344” A — — “A345”A — — “A346” A — — “A347” A — — “A348” A — — “A349” A — — “A350” A — —“A351” A — — “A352” A — —Description of In Vivo DataSystemic Lupus Erythematosus Mouse Model (SLE)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one,designated as “CPD. B”, was evaluated in an interferon-alpha acceleratedSLE mouse model. NZB/W F1 mice received i.v. injection at day 0 and day1 of 10⁸ infectious units of adenovirus (ADV-IFN-α) to deliver atransient overexpression on interferon alpha. Oral dosing of thedifferent group treatments was initiated on day 14 and continued dailyat 24 hour intervals until the end of the study. Treatment groupsconsisted of 20% Kleptose HPB in Na-citrate buffer (vehicle) or 0.1,0.3, 1, or 3 mg/kg of Cpd. B. Panel 1A shows the disease activity ofeach individual animal, calculated by the following Formula: Diseaseactivity=(0.5*(days with proteinuria of individual animal/mean of dayswith proteinuria of vehicle group)+0.5*(AUC of individual animal/meanAUC of vehicle group))*100. As shown in Panel 1B Cpd. B reduces thedisease activity in a dose-dependent manner with the percent reductionof the disease activity for each experimental condition documented. FIG.2 presents data from another interferon-alpha accelerated SLE experimentin mice. NZB/W F1 mice received i.v. injections at day 0 and day 1 of10⁸ infectious units of adenovirus (ADV-IFN-α) to deliver a transientoverexpression on interferon alpha. Oral dosing of the different grouptreatments (n=10) was initiated on day 14 and continued daily at 24 hourintervals until the end of the study. Treatment groups consisted of 20%Kleptose HPB in Na-citrate buffer (vehicle), 0.1, 0.3, 1, or 3 mg/kg ofCpd. B or Cell Cept®. FIG. 2 shows the mean protein creatinineratio+−SEM in the urine, at indicated time points, as a marker of kidneydamage. Statiscal analysis was performed using Two way ANOVA withBonferroni post test with all groups compared to vehicle treated group(*=p<0.05, **=p<0.01, ***=p<0.001).

Rat Collagen-Induced Arthritis Model

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one,designated as “CPD. A”, was evaluated in a collagen-induced arthritismodel in rats. Anesthetized female Lewis rats receivedsubcutaneous/intradermal injections of 300 μl of Freund's IncompleteAdjuvant containing 4 mg/ml bovine type II collagen, at the base of thetail and 2 sites on the back on days 0 and 6. FIG. 3 presents data fromthe oral dosing of the different group treatments was initiated on day 6and continued daily at 24 hour intervals, for 11 days up to day 16.Treatment groups consisted of 20% Hydroxy-Propyl-Beta Cyclodextrin inH₂O (vehicle) or 0.3, 1, 3, or 10 mg/kg of Cpd. A, or methotrexate (MTX)at 0.1 mg/kg. Caliper measurements of ankles were taken every daybeginning on day 9 (or day 0 of arthritis). Animals were sacrificed onday 17.

Mouse Collagen-Induced Arthritis Model

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one,designated as “CPD. A”, was evaluated in a collagen-induced arthritismodel in mice. Male DBA/1OlaHsd mice were injected intradermally at thebase of the tail with 150 μl of Freund's Complete Adjuvant containingbovine type II collagen on day 0 and on day 21. FIG. 4 presents datafrom this experiment. On day 18, mice were randomized by body weightinto treatment groups. Oral treatment was initiated after enrollment onday 18 and continued daily at 24 h intervals up to day 33. Mice weretreated with 20% Hydroxy-Propyl-Beta Cyclodextrin in H₂O (vehicle) orCpd. A at either 1, 3, 10, or 30 mg/kg or with methotrexate (MTX) at 0.5mg/kg. On study days 22-34 onset of arthritis occurred. Mice weresacrified on day 34. Clinical scores were given for each of the paws(right front, left front, right rear, left rear) on arthritis days18-34.

Mouse Passive Cutaneous Anaphylaxis (PCA)

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one,designated as “CPD. B”, was evaluated in a PCA model in mice.

In vivo anaphylaxis mediated through the FcεRI receptor is amast-cell-dependent allergic response to local or systemic exposure toallergens, which cross-link and activate antigen-specific IgE bound tothe FcεRI on the mast cell surface leading to mast cell activation anddegranulation. The murine PCA model mimicks these events in vivo and canbe used for testing the efficacy of newly developed compounds targetingtyrosine kinases that are downstream of FcεRI like BTK. FIG. 5 presentsdata from experiments where 10-week old female BALB/c mice were injectedintradermally with immunoglubulin E (IgE) directed against the hapten2,4-dinitrophenyl (DNP). 24 h after sensitization, mice were challengedby systemic administration of DNP coupled to human serum albumin (HSA),together with Evan's blue dye. Mice were dosed orally with three dosesof Cpd B. 1 h before challenge. Evan's blue extravasation was measuredin the back 30 minutes after the challenge.

Anti-IgD-Induced CD69 Upregulation in Mouse Whole Blood

1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one,designated as “CPD. B”, was evaluated anti-IgD-induced CD69 upregulationin mouse whole blood and these data are presented in FIG. 6. BCRactivation induces the expression of the surface cluster ofdifferentiation 69 (CD69) which is the earliest inducible cell surfaceglycoprotein acquired during lymphoid activation and is currently usedas a marker for B cell activation both in vitro and ex vivo. FemaleC57Bl/6 mice were administered orally with Cyclodextrin or 1.19, 3.96 or11.9 mg/kg of Cpd. A 1 h before blood collection. Half an hour afterintraperitoneal injection of heparin, blood was collected in heparinizedtubes and B cells were stimulated with 10 μl of PBS or polyclonal goatanti-mouse IgD antiserum for 4 h. CD69 upregulation in individual cellswas determined by flow cytometric analysis using rat anti-mouseB220-PerCP-Cy5.5 and hamster anti-mouse CD69-PE monoclonal antibodiesfor immunostaining.

What is claimed is:
 1. A compound of formula I

in which X denotes CH, R¹ denotes NH₂, or CONH₂, R² denotes Ar¹ or Het¹,R³ denotes NR⁵[C(R⁵)₂]_(n)Het², NR⁵[C(R⁵)₂]_(n)Cyc, Het²,O[C(R⁵)₂]_(n)Ar², NR⁵[C(R⁵)₂]_(n)Ar², O[C(R⁵)₂]_(n)Het²,NR⁵(CH₂)_(p)NR⁵R⁶, O(CH₂)_(p)NR⁵R⁶ or NR⁵(CH₂)_(p)CR⁷R⁸NR⁵R⁶, R⁴ denotesH, CH₃ or NH₂, R⁵ denotes H or alkyl having 1, 2, 3 or 4 C atoms, R⁶N(R⁵)₂CH₂CH═CHCONH, Het³CH₂CH═CHCONH, CH₂═CHCONH(CH₂)n,Het⁴(CH₂)_(n)COHet³-diyl-CH₂CH═CHCONH, HC≡CCO, CH₃C≡CCO, CH₂═CH—CO,CH₂═C(CH₃)CONH, CH₃CH═CHCONH(CH₂)_(n), N≡CCR⁷R⁸CONH(CH₂)_(n),Het⁴NH(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH,Het⁴(CH₂)_(p)CONH(CH₂CH₂O)_(p)(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH,CH₂═CHSO₂, ACH═CHCO, CH₃CH═CHCO,Het⁴(CH₂)_(p)CONH(CH₂)_(p)Het³-diyl-CH₂CH═CHCONH, Ar³CH═CHSO₂,CH₂═CHSO₂NH or N(R⁵)CH₂CH═CHCO, R⁷, R⁸ denote together alkylene having2, 3, 4, or 5 C atoms, Ar¹ denotes phenyl or naphthyl, each of which isunsubstituted or mono-, di- or trisubstituted by R⁶, Hal, (CH₂)_(n)NH₂,CONHAr³, (CH₂)_(n)NHCOA, O(CH₂)_(n)Ar³, OCyc, A, COHet³, OA and/or OHet³(CH₂), Ar² denotes phenyl, naphthyl or pyridyl each of which isunsubstituted or mono-, di- or trisubstituted by R⁶, Hal, OAr³,(CH₂)_(n)NH₂, (CH₂)_(n)NHCOA and/or Het³, Ar³ denotes phenyl, which isunsubstituted or mono-, di- or trisubstituted by OH, OA, Hal, CN and/orA, Het¹ denotes a mono- or bicyclic saturated, unsaturated or aromaticheterocycle having 1 to 4 N, O and/or S atoms, which may beunsubstituted or mono-, di- or trisubstituted by R⁶, O(CH₂)_(n)Ar³and/or (CH₂)_(n)Ar³, Het² each independently denotes a mono- or bicyclicsaturated heterocycle having 1 to 4 N, O and/or S atoms, which may beunsubstituted or mono-, di- or trisubstituted by R⁶, Het³, CycSO₂, OH,Hal, COOH, OA, COA, COHet³, CycCO, SO₂ and/or ═O, Het³ eachindependently denotes a monocyclic unsaturated, saturated or aromaticheterocycle having 1 to 4 N, O and/or S atoms, which may beunsubstituted or mono-, di- or trisubstituted by Hal, A and/or ═O, Het⁴each independently denotes a bi- or tricyclic unsaturated, saturated oraromatic heterocycle having 1 to 4 N, O and/or S atoms, which may beunsubstituted or mono-, di-, tri- or tetrasubstituted by A, NO₂, Haland/or ═O, Cyc each independently denotes cyclic alkyl having 3, 4, 5 or6 C atoms, which is unsubstituted, monosubstituted or disubstituted byR⁶ and/or OH and which may comprise a double bond, A each independentlydenotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7 Hatoms may be replaced by F and/or Cl and/or in which one or twonon-adjacent CH₂ and/or CH-groups may be replaced by O, NH and/or by N,Hal each independently denotes F, Cl, Br or I, n each independentlydenotes 0, 1, 2, 3 or 4, p each independently denotes 1, 2, 3, 4, 5 or6, or pharmaceutically acceptable salts, tautomers or stereoisomersthereof, including mixtures thereof in all ratios.
 2. The compoundaccording to claim 1, wherein Het¹ denotes piperidinyl, piperazinyl,pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl,benzo-1,3-dioxolyl, indazolyl, azabicyclo[3.2.1]octyl,azabicyclo[2.2.2]octyl, imidazolidinyl, azetidinyl, azepanyl,benzo-2,1,3-thiadiazolyl, tetrahydrofuryl, dioxolanyl,tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl,dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl, dihydropyridylor dihydrobenzodioxinyl, each of which is unsubstituted or mono-, di- ortrisubstituted by R⁶, O(CH₂)_(n)Ar³ and/or (CH₂)_(n)Ar³ orpharmaceutically acceptable salts, tautomers or stereoisomers thereof,including mixtures thereof in all ratios.
 3. The compound according toclaim 2, wherein Het¹ denotes pyrazolyl, pyridyl, pyrimidinyl,dihydropyridyl or dihydrobenzodioxinyl, each of which is unsubstitutedor mono-, di- or trisubstituted by R⁶, O(CH₂)_(n)Ar³ and/or(CH₂)_(n)Ar³, or pharmaceutically acceptable salts, tautomers orstereoisomers thereof, including mixtures thereof in all ratios.
 4. Thecompound according to claim 1, wherein Het² denotes piperidinyl,piperazinyl, pyrrolidinyl, morpholinyl, azabicyclo[3.2.1]octyl,azabicyclo[2.2.2]octyl, 2,7-diazaspiro[3.5]nonyl,2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[4.4]nonyl,3-azabicylo[3.1.0]hexyl, 2-azaspiro[3.3]heptyl, 6-azaspiro[3.4]octyl,7-azaspiro[3.5]nonyl, 5-azaspiro[3.5]nonyl, imidazolidinyl, azetidinyl,azepanyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl,tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydropyridyl, each ofwhich is unsubstituted or mono-, di- or trisubstituted by R⁶, Het³,CycSO₂, OH, OA, COA, COHet³, CycCO, SO₂ and/or ═O, or pharmaceuticallyacceptable salts, tautomers or stereoisomers thereof, including mixturesthereof in all ratios.
 5. The compound according to claim 1, whereinHet³ denotes piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl,oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, imidazolidinyl,azetidinyl, azepanyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl,dihydropyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl,tetrahydropyrazolyl, tetrahydropyridyl or dihydropyridyl, each of whichmay be unsubstituted or mono-, di- or trisubstituted by Hal, A and/or═O, or pharmaceutically acceptable salts, tautomers or stereoisomersthereof, including mixtures thereof in all ratios.
 6. The compoundaccording to claim 5, wherein Het³ denotes piperidinyl, pyrrolidinyl,morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,pyrimidinyl, dihydropyrrolyl, dihydropyrazolyl or dihydropyridyl, eachof which may be unsubstituted or mono-, di- or trisubstituted by Hal, Aand/or ═O, or pharmaceutically acceptable salts, tautomers orstereoisomers thereof, including mixtures thereof in all ratios.
 7. Thecompound according to claim 1, wherein Het⁴ denoteshexahydrothieno[3,4-d]imidazolyl, benzo[c][1,2,5]oxadiazolyl or5H-dipyrrolo[1,2-c:2′, 1′-f][1,3,2]diazaborinin-4-ium-uidyl, each ofwhich may be unsubstituted or mono-, di-, tri- or tetrasubstituted by A,NO₂, Hal and/or ═O, or pharmaceutically usable acceptable salts,tautomers and or stereoisomers thereof, including mixtures thereof inall ratios.
 8. The compound according to claim 1, wherein X denotes CH,R¹ denotes NH₂, or CONH₂, R² denotes Ar¹ or Het¹, R³ denotesNR⁵[C(R⁵)₂]_(n)Het², NR⁵[C(R⁵)₂]_(n)Cyc, Het², O[C(R⁵)₂]_(n)Ar²,NR⁵[C(R⁵)₂]_(n)Ar², O[C(R⁵)₂]_(n)Het², NR⁵(CH₂)_(p)NR⁵R⁶,O(CH₂)_(p)NR⁵R⁶NR⁵(CH₂)_(p)CR⁷R⁸NR⁵R⁶, R⁴ denotes H, R⁵ eachindependently denotes H or alkyl having 1, 2, 3 or 4 C atoms, R⁶ eachindependently denotes N(R⁵)₂CH₂CH═CHCONH, Het³CH₂CH═CHCONH,CH₂═CHCONH(CH₂)_(n), Het⁴(CH₂)_(n)COHet³-diyl-CH₂CH═CHCONH, HC≡CCO,CH₃C≡CCO, CH₂═CH—CO, CH₂═C(CH₃)CONH, CH₃CH═CHCONH(CH₂)_(n),N≡CCR⁷R⁸CONH(CH₂)_(n), Het⁴NH(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH,Het⁴(CH₂)_(p)CONH(CH₂CH₂O)_(p)(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH,CH₂═CHSO₂, ACH═CHCO, CH₃CH═CHCO,Het⁴(CH₂)_(p)CONH(CH₂)_(p)Het³-diyl-CH₂CH═CHCONH, Ar³CH═CHSO₂,CH₂═CHSO₂NH or N(R⁵)CH₂CH═CHCO, R⁷, R⁸ denote together alkylene having2, 3, 4, or 5 C atoms, Ar¹ denotes phenyl or naphthyl, each of which isunsubstituted or mono-, di- or trisubstituted by R⁶, Hal, (CH₂)_(n)NH₂,CONHAr³, (CH₂)_(n)NHCOA, O(CH₂)_(n)Ar³, OCyc, A, COHet³, OA and/or OHet³(CH₂), Ar² denotes phenyl or naphthyl, each of which is unsubstituted ormono-, di- or trisubstituted by R⁶, Hal, OAr³, (CH₂)_(n)NH₂,(CH₂)_(n)NHCOA and/or Het³, Ar³ each independently denotes phenyl, whichis unsubstituted or mono-, di- or trisubstituted by OH, OA, Hal, CNand/or A, Het¹ denotes piperidinyl, piperazinyl, pyrrolidinyl,morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl,tetrazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl,benzimidazolyl, benzotriazolyl, indolyl, benzo-1,3-dioxolyl, indazolyl,azabicyclo[3.2.1]octyl, aza-bicyclo[2.2.2]octyl, imidazolidinyl,azetidinyl, azepanyl, benzo-2,1,3-thiadiazolyl, tetrahydrofuryl,dioxolanyl, tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl,dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl, dihydropyridylor dihydrobenzodioxinyl, each of which is unsubstituted or mono-, di- ortrisubstituted by R⁶, O(CH₂)_(n)Ar³ and/or (CH₂)_(n)Ar³, Het² eachindependently denotes piperidinyl, piperazinyl, pyrrolidinyl,morpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl,2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[4.5]decyl,2,7-diazaspiro[4.4]nonyl, 3-azabicylo[3.1.0]hexyl,2-azaspiro[3.3]heptyl, 6-azaspiro[3.4]octyl, 7-azaspiro[3.5]nonyl,5-azaspiro[3.5]nonyl, imidazolidinyl, azetidinyl, azepanyl,tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, tetrahydroimidazolyl,tetrahydropyrazolyl, tetrahydropyridyl, each of which is unsubstitutedor mono-, di- or trisubstituted by R⁶, Het³, CycSO₂, OH, OA, COA,COHet³, CycCO, SO₂ and/or ═O, Het³ each independently denotespiperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, furyl, thienyl,pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl,thiadiazolyl, pyridazinyl, pyrazinyl, imidazolidinyl, azetidinyl,azepanyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl,dihydropyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl,tetrahydropyrazolyl, tetrahydropyridyl or dihydropyridyl, each of whichmay be unsubstituted or mono-, di- or trisubstituted by Hal, A and/or═O, Het⁴ each independently denotes hexahydrothieno[3,4-d]imidazolyl,benzo[c][1,2,5]oxadiazolyl or 5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-uidyl, each of which may be unsubstitutedor mono-, di-, tri- or tetrasubstituted by A, NO₂, Hal and/or ═O, Cyceach independently denotes cyclic alkyl having 3, 4, 5 or 6 C atoms,which is unsubstituted or monosubstituted by R⁶ and which may comprise adouble bond, A each independently denotes unbranched or branched alkylhaving 1-10 C atoms, in which 1-7 H atoms may be replaced by F and/or Cland/or in which one or two non-adjacent CH₂ and/or CH-groups may bereplaced by O, NH and/or by N, Hal each independently denotes F, Cl, Bror I, n each independently denotes 0, 1, 2, 3 or 4, p each independentlydenotes 1, 2, 3, 4, 5 or 6, or pharmaceutically acceptable salts,tautomers or stereoisomers thereof, including mixtures thereof in allratios.
 9. The compound according to claim 1, which is selected from thegroup consisting of the compounds of the following table No. ChemicalName “A76” 1-(4-(((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one, “A149”N-(3-((2-amino-3-(4-(benzyloxy)phenyl)pyridin-4-yl)oxy)phenyl)acrylamide, “A151”(E)-N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide, “A152”(E)-N-(3-((2-amino-3-(4-(benzyloxy)phenyl)pyridin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide, “A158”N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)-4-fluorophenyl)acrylamide, “A243”N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3- yl)phenyl)acrylamide,“A244” N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide, “A272”3-(3-acrylamidophenyl)-4-(4-phenoxyphenoxy)picolinamide, “A300”3-(3-aminophenyl)-4-(4-phenoxyphenoxy)pyridin-2-amine, “A310”N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3- yl)phenyl)propionamide,“A313” 4-(3-aminophenoxy)-3-(4-phenoxyphenyl)pyridin-2-amine, and “A328”3-(4-phenoxyphenyl)-4-(3-propionamidophenoxy)picolinamide

or pharmaceutically acceptable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios.
 10. A process for thepreparation of a compound of formula I according to claim 1 orpharmaceutically acceptable salts, tautomers and stereoisomers thereof,said process comprising: reacting a) a compound of the formula A

in which R¹ has the meaning indicated in claim 1, with a compound of theformula B

in which R², R³, R⁴ and R^(4′) have the meanings indicated in claim 1and L denotes Cl, Br, I or a free or reactively functionally modified OHgroup, and/or a base or acid of the formula A is converted into one ofits salts.